Identification of homozygous deletion in ACAN and other candidate variants in familial classical Hodgkin lymphoma by exome sequencing

Tutkimuksessamme tarkastelimme Lähi-idästä lähtöisin olevaa perhettä, jossa kolmella viidestä lapsesta on todettu nuorellä iällä klassinen Hodgkinin lymfooma (cHL). Perinnöllinen alttius cHL:lle tunnetaan huonosti, eikä taudille mahdollisesti altistavia geenimuutoksia ole aiemmin raportoitui kuin yksi kappale. Geenimuutosten selvittämiseksi eksomisekvensoimme kolmen sairastuneen lapsen verinäytteestä eristetyn DNA:n ja poimimme joukosta kaikkien kolmen jakamat muutokset. Suodatimme lasten jakamien DNA-muutosten joukosta pois omissa vertailujoukoissamme ja useissa julkisissa tietokannoissa esiintyvät geneettiset muutokset ja arvioimme jäljellejääneiden muutosten haitallisuutta kahdella laskennallisella priorisaatioalgoritmilla. Näin saimme järjestettyä jäljelle jääneet 35 jaettua muutosta laskennalliseen haitallisuusjärjestykseen. Jaetuista muutoksista merkittävimmäksi nousi ACAN-geenissä oleva homotsygoottinen 57 emäksen pituinen deleetio c.2836_2892del, jota ei ole aiemmin liitytty cHL-fenotyyppiin

Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans

Clonal hematopoiesis driven by somatic heterozygous TET2 loss is linked to malignant degeneration via consequent aberrant DNA methylation, and possibly to cardiovascular disease via increased cytokine and chemokine expression as reported in mice. Here, we discover a germline TET2 mutation in a lymphoma family. We observe neither unusual predisposition to atherosclerosis nor abnormal pro-inflammatory cytokine or chemokine expression. The latter finding is confirmed in cells from three additional unrelated TET2 germline mutation carriers. The TET2 defect elevates blood DNA methylation levels, especially at active enhancers and cell-type specific regulatory regions with binding sequences of master transcription factors involved in hematopoiesis. The regions display reduced methylation relative to all open chromatin regions in four DNMT3A germline mutation carriers, potentially due to TET2-mediated oxidation. Our findings provide insight into the interplay between epigenetic modulators and transcription factor activity in hematological neoplasia, but do not confirm the putative role of TET2 in atherosclerosis.Peer reviewe

Comprehensive evaluation of coding region point mutations in microsatellite-unstable colorectal cancer

Microsatellite instability (MSI) leads to accumulation of an excessive number of mutations in the genome, mostly small insertions and deletions. MSI colorectal cancers (CRCs), however, also contain more point mutations than microsatellite-stable (MSS) tumors, yet they have not been as comprehensively studied. To identify candidate driver genes affected by point mutations in MSI CRC, we ranked genes based on mutation significance while correcting for replication timing and gene expression utilizing an algorithm, MutSigCV. Somatic point mutation data from the exome kit-targeted area from 24 exome-sequenced sporadic MSI CRCs and respective normals, and 12 whole-genome-sequenced sporadic MSI CRCs and respective normals were utilized. The top 73 genes were validated in 93 additional MSI CRCs. The MutSigCV ranking identified several well-established MSI CRC driver genes and provided additional evidence for previously proposed CRC candidate genes as well as shortlisted genes that have to our knowledge not been linked to CRC before. Two genes, SMARCB1 and STK38L, were also functionally scrutinized, providing evidence of a tumorigenic role, for SMARCB1 mutations in particular. © 2018 The Authors. Published under the terms of the CC BY 4.0 licensePeer reviewe

Using an abdominal phantom to teach urology residents ultrasound-guided percutaneous needle placement

ABSTRACT Introduction: To assess the effect of a hands-on ultrasound training session to teach urologic trainees ultrasound-guided percutaneous needle placement. Materials and methods: University of California, San Francisco (UCSF) urology residents completed a time trial, placing a needle into a phantom model target under ultrasound guidance. Participants were randomized into three educational exposure groups: Group 1's time trial occurred prior to any teaching intervention, group 2's after experiencing a hands-on training module, and group 3's after exposure to both the training module and one-on-one attending feedback. Needle placement speed and accuracy as well as trainees' perceived confidence in utilizing ultrasound were measured. Results: The study cohort consisted of 15 resident trainees. Seven were randomized to group 1, three to group 2, and five to group 3. All residents reported minimal prior ultrasound experience. Their confidence in using ultrasound improved significantly after completing the training module with the most significant improvement seen among junior residents. Time to needle placement was fastest after receiving attending feedback (46.6sec in group 3 vs. 82.7sec in groups 1 and 2, p<0.01). Accuracy also improved with attending feedback, though the number of repositioning attempts did not differ significantly between groups. Conclusions: A hands-on training module and use of an abdominal phantom trainer increased resident confidence and skill in their use of ultrasound to guide percutaneous needle positioning. Attending feedback is critical for improving accuracy in needle guidance toward a target. Ultrasound-guided needle positioning is a teachable skill and can be applicable to multiple urologic procedures

Surface water ponding on clayey soils managed by conventional and conservation tillage in boreal conditions

Surface water ponding and crop hampering due to soil wetness was monitored in order to evaluate the effects of conservation tillage practices and perennial grass cover on soil infiltrability for five years in situ in gently sloping clayey fields. Thirteen experimental areas, each having three experimental fields, were established in southern Finland. The fields belonged to: autumn mouldboard ploughing (AP), conservation tillage (CT) and perennial grass in the crop rotation (PG). In the third year, direct drilled (DD) fields were established in five areas. Excluding PG, mainly spring cereals were grown in the fields. Location and surface area of ponded water (in the spring and autumn) as well as hampered crop growth (during June-July) were determined in each field by using GPS devices and GIS programs. Surface water ponding or crop hampering occurred when the amount of rainfall was clearly greater than the long-term average. The mean of the relative area of the ponded surface water, indicating the risk of surface runoff, and hampered crop growth was larger in the CT fields than in the AP fields. The differences between means were, however, not statistically significant. Complementary soil physical measurements are required to investigate the reasons for the repeated surface water ponding.;Etelä-Suomessa kartoitettiin 13 koealueella pintaveden ja kasvien kasvua haittaavan maan märkyyden esiintymistä viiden vuoden ajan. Tavoitteena oli arvioida kevennetyn muokkauksen ja monivuotisen nurmen vaikutusta veden imeytymiseen savimaahan käytännön viljelyssä olleilla peltolohkoilla. Jokaisella koealueella oli kolme lohkoa, joista yksi syyskynnettiin, toinen syyskultivoitiin ja kolmannella viljeltiin monivuotista nurmea viljelykierrossa. Kolmantena koevuonna viidellä koealueella seurantaan otettiin mukaan suorakylvölohko. Monivuotista nurmea lukuun ottamatta lohkoilla viljeltiin kevätkylvöisiä siemenkasveja. Lohkoilta määritettiin keväisin ennen kylvöä, kesällä ennen kasvuton tähkimistä ja syksyllä syysmuokkauksen jälkeen pintaveden peittämä ala ja kasvuston ala, joka oli kärsinyt märkyydestä, käyttämällä GPS -laitetta. Aineisto käsiteltiin GIS -ohjelmistolla, minkä jälkeen voitiin laskea pintaveden peittämän tai maan märkyydestä kärsineen alan suhde koko lohkon alaan. Pellolla oli pintavettä (lätäköitä) tai kasvusto kärsi maan märkyydestä, kun koealueella satoi selvästi enemmän kuin keskimäärin. Keskimäärin pintaveden peittämän tai märkyydestä kärsineen kasvuston alan osuus koko lohkon alasta oli syyssänkimuokattaessa suurempi kuin syyskynnettäessä. Keskiarvojen erot eivät olleet kuitenkaan tilastollisesti merkitseviä. Mittausten perusteella ei voitu päätellä syytä toistuvaan pintaveden esiintymiseen. Syyn selvittäminen edellyttää maan fysikaalisten ominaisuuksien määrittämistä

Soil type classification with permittivity and electrical conductivity surveys

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