The main challenge for gaining biological insights from genetic associations is identifying which genes and pathways explain the associations. Here we present DEPICT, an integrative tool that employs ...predicted gene functions to systematically prioritize the most likely causal genes at associated loci, highlight enriched pathways and identify tissues/cell types where genes from associated loci are highly expressed. DEPICT is not limited to genes with established functions and prioritizes relevant gene sets for many phenotypes.
Many patients with aggressive B-cell lymphomas and high clinical risk score still die of lymphoma after conventional R-CHOP chemoimmunotherapy. We hypothesized that intensified chemoimmunotherapy ...including systemic central nervous system (CNS) prophylaxis improves outcome and reduces the incidence of CNS-related events.
Inclusion criteria were age 18–65 years, primary diffuse large B-cell lymphoma or grade III follicular lymphoma without clinical signs of CNS disease and negative cerebrospinal fluid cytology, age-adjusted International Prognostic Index 2–3 and WHO performance score 0–3. Treatment consisted of six courses of R-CHOEP-14 followed by a course of high-dose cytarabine and a course of high-dose methotrexate. Primary end point was failure-free survival (FFS) at 3 years.
A total of 156 eligible patients with a median age of 54 years (range 20–64) were included. Three toxic deaths were observed. Three-year overall survival (OS) and FFS rates (median observation time 52 months for survivors) were 81% and 65%, respectively. Seven patients experienced CNS relapse, all within 6 months.
The results are promising with favorable 3-year OS and FFS rates, a low toxic death rate and a lower than expected number of CNS events. CNS progression might be further reduced by earlier CNS prophylaxis.
NCT01502982.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Aquatic ecosystems face a variety of anthropogenic pressures, urging the development of efficient biological indicators. In addition to local environmental conditions, the community structure of ...indicator organisms is affected by spatial processes, such as high and limited dispersal rates. Understanding the relative roles of environmental factors and spatial processes for ecological communities should thus be associated with bioassessment practices. We examined the main drivers, both environmental and spatial, influencing community structure and several indices derived from diatom communities. We sampled 81 stony littoral sites in a large boreal lake system (305km2), where relatively large gradients in water chemistry (35 variables measured) exist, but no dispersal limitation can be expected. Instead, high dispersal rates should interfere with species sorting. Our response variables, including commonly-used diatom indices, diversity indices and taxonomic distinctness indices, were better explained by pure effects of spatial variables and shared effects of spatial and environmental variables than by pure effects of environmental variables. Thus, high dispersal rates between sites are likely to interfere with environmental filtering and can result in clear spatial structures in index values used in bioassessment. Bioassessment should thus acknowledge the importance of spatial processes and not take it for granted that only local environmental conditions determine index values. Failure to consider high dispersal rates may lead to biased information about the state of freshwater ecosystems. The same idea should also be considered in systems with similarly highly-connected sets of bioassessment sites, such as marine coastal systems and stream networks.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The diagnostic yield of exome and genome sequencing remains low (8-70%), due to incomplete knowledge on the genes that cause disease. To improve this, we use RNA-seq data from 31,499 samples to ...predict which genes cause specific disease phenotypes, and develop GeneNetwork Assisted Diagnostic Optimization (GADO). We show that this unbiased method, which does not rely upon specific knowledge on individual genes, is effective in both identifying previously unknown disease gene associations, and flagging genes that have previously been incorrectly implicated in disease. GADO can be run on www.genenetwork.nl by supplying HPO-terms and a list of genes that contain candidate variants. Finally, applying GADO to a cohort of 61 patients for whom exome-sequencing analysis had not resulted in a genetic diagnosis, yields likely causative genes for ten cases.
Abstract Breast lymphomas comprise a rare group of malignant breast tumors. Among these, a new entity has emerged as a potentially under-diagnosed disease. Breast implant-associated anaplastic large ...cell lymphoma (BI-ALCL) most often manifests as a late periprosthetic effusion between 1 to 10 years after the implantation of silicone or saline-filled breast prostheses. BI-ALCL is an anaplastic lymphoma kinase-negative T-cell lymphoma that has a distinctively different clinical course than other breast lymphomas or ALCLs. Diagnosis is based on aspiration of the effusion around the implant and CD30 positivity of the sample. Every periprosthetic effusion after breast augmentation or reconstruction using implants should be considered as potential BI-ALCL until proven otherwise. The majority of cases at diagnosis are in the in situ stage, i.e., confined to the lumen around the prosthesis. Most patients have an excellent prognosis when complete removal of the capsule and prosthesis with negative margins is achieved surgically. Some patients, however, develop infiltrative disease with a potentially life-threatening clinical course. Treatment planning regarding the extent of surgery and role of adjuvant therapy, especially in advanced cases, requires further investigation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The autosomal dominant cerebellar ataxias, referred to as spinocerebellar ataxias in genetic nomenclature, are a rare group of progressive neurodegenerative disorders characterized by loss of balance ...and coordination. Despite the identification of numerous disease genes, a substantial number of cases still remain without a genetic diagnosis. Here, we report five novel spinocerebellar ataxia genes, FAT2, PLD3, KIF26B, EP300, and FAT1, identified through a combination of exome sequencing in genetically undiagnosed families and targeted resequencing of exome candidates in a cohort of singletons. We validated almost all genes genetically, assessed damaging effects of the gene variants in cell models and further consolidated a role for several of these genes in the aetiology of spinocerebellar ataxia through network analysis. Our work links spinocerebellar ataxia to alterations in synaptic transmission and transcription regulation, and identifies these as the main shared mechanisms underlying the genetically diverse spinocerebellar ataxia types.
Iron (Fe) is an important element in aquatic ecosystems worldwide because it is intimately tied with multiple abiotic and biotic phenomena. Here, we give a survey of manifold influences of Fe, and ...the key factors affecting it in the boreal catchments and their waters. It includes the perspectives of biogeochemistry, hydrology, ecology, and river basin management. We emphasize views on the dynamics and impacts of different forms of Fe in riverine environments, including organic colloids and particles, as well as inorganic fractions. We also provide perspectives for land use management in boreal catchments and suggest guidelines for decision making and water management. Based on our survey, the main emphases of water protection and management programs should be (i) prevention of Fe mobilization from soil layers by avoiding unnecessary land-use activities and minimizing soil disturbance in high-risk areas; (ii) disconnecting Fe-rich ground water discharge from directly reaching watercourses; and (iii) decreasing transport of Fe to watercourses by applying efficient water pollution control approaches. These approaches may require specific methods that should be given attention depending on catchment conditions in different areas. Finally, we highlight issues requiring additional research on boreal catchments. A key issue is to increase our understanding of the role of Fe in the utilization of DOM in riverine food webs, which are typically highly heterotrophic. More knowledge is needed on the metabolic and behavioral resistance mechanisms that aquatic organisms, such as algae, invertebrates, and fish, have developed to counter the harmful impacts of Fe in rivers with naturally high Fe and DOM concentrations. It is also emphasized that to fulfil the needs presented above, as well as to develop effective methods for decreasing the harmful impacts of Fe in water management, the biogeochemical processes contributing to Fe transport from catchments via rivers to estuaries should be better understood.
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•Fe has a key role in biogeochemical and ecological contexts in boreal catchments.•Fe has many harmful impacts on aquatic organisms and ecosystems.•Drivers of Fe transport should be better known in water management.•Catchment-scale approaches are required to create effective management of Fe.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Testicular lymphoma is a rare malignancy affecting mainly elderly men, the majority representing diffuse large B-cell lymphoma (DLBCL). Its relapse rate is higher than that of nodal DLBCL, often ...affecting the central nervous system (CNS) with dismal prognosis.
We searched for patients with testicular DLBCL (T-DLBCL) involvement from the pathology databases of Southern Finland University Hospitals and the Danish Lymphoma Registry. Clinical information was collected, and outcomes between treatment modalities were evaluated. Progression-free survival (PFS), disease-specific survival (DSS) and overall survival (OS) were assessed using Kaplan–Meier and Cox proportional hazards methods.
We identified 235 patients; of whom, 192 were treated with curative anthracycline-based chemotherapy. Full survival data were available for 189 patients. In univariate analysis, intravenous CNS-directed chemotherapy, and irradiation or orchiectomy of the contralateral testis translated into favourable PFS, DSS and OS, particularly among the elderly patients (each p ≤ 0.023). Intrathecal chemotherapy had no impact outcome. In multivariate analyses, the advantage of intravenous CNS-directed chemotherapy (hazard ration HR for OS, 0.419; 95% confidence interval CI, 0.256–0.686; p = 0.001) and prophylactic treatment of contralateral testis (HR for OS, 0.514; 95% CI, 0.338–0.782; p = 0.002) was maintained. Rituximab improved survival only among high-risk patients (International Prognostic Index≥3, p = 0.019). The cumulative risk of CNS progression was 8.4% and did not differ between treatment modalities.
The results support the use of CNS-directed chemotherapy and prophylactic treatment of the contralateral testis in patients with T-DLBCL involvement. Survival benefit appears resulting from better control of systemic disease rather than prevention of CNS progression.
•Intravenous central nervous system (CNS)–directed chemotherapy translates to superior survival in testicular lymphoma.•Phophylactic treatment of contralateral testis is associated with improved survival.•Intrathecal CNS-directed chemotherapy does not have impact on survival.•The benefit of rituximab is seen only among the patients with high International Prognostic Index.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Electric circuits containing vacuum tubes form an integral part of various audio equipment, such as guitar amplifiers, certain equalizers, microphone preamplifiers, and dynamic range compressors. ...Although most audio signal processing operations are straightforward to implement with modern computers, real-time digital simulation of vacuum tubes poses a significant challenge due to the dynamic nonlinearities of the tube circuits. Most of the current vacuum-tube emulators model the unidirectional signal path of the circuit using linear filters and nonlinear waveshapers, possibly with signal-dependent parameters. This paper introduces a physical model of a tube stage circuit using wave digital filters. In contrast to previous unidirectional signal models, the wave digital model implements bidirectional signal propagation. This allows realistic simulation of interesting dynamical nonlinearities, such as the bias variation under reactive load. The new model is an extension of the wave digital tube presented in ¿Wave digital simulation of a vacuum-tube amplifier¿ (M. Karjalainen and J. Pakarinen Proc. Int. Conf. Acoustics, Speech, Signal Processing, 2006, vol. V, pp. 153-156). In particular, the enhanced model for the tube grid-to-cathode connection enables the simulation of interstage coupling and blocking distortion.
Disks in binary systems can cause exotic eclipsing events. MWC 882 (BD -22 4376, EPIC 225300403) is such a disk-eclipsing system identified from observations during Campaign 11 of the K2 mission. We ...propose that MWC 882 is a post-Algol system with a B7 donor star of mass in a 72-day orbit around an A0 accreting star of mass . The disk around the accreting star occults the donor star once every orbit, inducing 19-day long, 7% deep eclipses identified by K2 and subsequently found in pre-discovery All-Sky Automated Survey and All Sky Automated Survey for Supernovae observations. We coordinated a campaign of photometric and spectroscopic observations for MWC 882 to measure the dynamical masses of the components and to monitor the system during eclipse. We found the photometric eclipse to be gray to 1%. We found that the primary star exhibits spectroscopic signatures of active accretion, and we observed gas absorption features from the disk during eclipse. We suggest that MWC 882 initially consisted of a 3.6 M donor star transferring mass via Roche lobe overflow to a 2.1 M accretor in a 7-day initial orbit. Through angular momentum conservation, the donor star is pushed outward during mass transfer to its current orbit of 72 days. The observed state of the system corresponds with the donor star having left the red giant branch ∼0.3 Myr ago, terminating active mass transfer. The present disk is expected to be short-lived (102 yr) without an active feeding mechanism, presenting a challenge to this model.
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