Abstract: Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.

Abstract: Im Rahmen von Peer-Begleitung (engl. peer support) erhält eine Person mit einer psychischen Erkrankung Unterstützung von einer Person, die selbst Erfahrung mit Krisen und/oder psychiatrischen Diagnosen gemacht und damit einen guten Umgang gefunden hat. „Peer-Begleiter/innen helfen als Betroffene Betroffenen“, erklärt Stefan Bilmayer, UPSIDES Peer-Begleiter am deutschen Standort Ulm/Günzburg.

Abstract: Background: PCGTCL is a rare disorder, accounting for 〈 1% of all lymphomas. In part given the rarity, timely and accurate diagnosis (dx) remains challenging. Moreover, PCGTCL is typically characterized by a highly aggressive course. We conducted a multi-institutional, retrospective analysis to delineate pathology, patient (pt) characteristics, treatment patterns & outcomes of PCGDTCL in the modern era. Methods: We collected detailed information on pts with PCGDTCL dx between 2000 - 2017 across 10 academic centers. Pathologic data, including IHC & flow characteristics on de-identified pathology reports, were reviewed centrally by an expert dermatopathologist (MP). A pathologic tier was assigned to each case based on fidelity to the following pre-defined minimum criteria: flow cytometric evidence of gamma and/or delta protein-expressing lymphoma or histopathologic evidence of gamma and/or delta protein expression & at least 50% atypical lymphocytes positive for gamma/delta immunostain (IHC) with tissue representative of entire lesion. The presence of 〉 25% CD30 positivity of malignant lymphocytes was an exclusion criterion. Further, PCR evidence of TCR gamma monoclonality or TCR beta/betaF1 negativity alone were inadequate for inclusion with confirmation of gamma/delta phenotype (especially IHC) being key for inclusion. A clinical tier was also assigned to each case based on group consensus. A composite score was derived by combining pathologic & clinical tiers, with those fitting a pre-determined score threshold included in the primary analysis. Univariate (UVA) associations were derived via Cox model for associations with survival. Results: Collectively, all centers submitted a total of 80 cases that were dx & treated locally as PCGDTCL. 48 (60%) cases met pre-defined criteria for inclusion of bona fide dx of PCGTCL. 26 (33%) cases had insufficient composite scores and were grouped in a 2nd tier & 6 cases had incomplete follow-up data and were unsuitable for analysis. The most common reason for placement in the 2nd tier was negativity for gamma/delta IHC or lack of documentation of such testing (n=16). Among the top tier of 48 veritable cases, 32 pts (67%) were male, 39 (81%) white & 4 (8%) black. Median age was 62 years (range 20-88). 19 (40%) pts had B symptoms at dx; ECOG performance status (PS) 0 in 12 pts (25%) & 1-3 in 22 cases (45%) (unknown 29%); anemia was present in 21 pts (44%) & LDH increased in 22 (46%). Bone marrow was involved in only 3 pts (6%) & hemophagocytic syndrome was present at dx in 6 pts (12%). Frontline therapy was heterogeneous (Table 1) with the most common therapies being bexarotene alone in 8 pts; UV therapy in 6 pts; and CHOP in 4 pts. Furthermore, there was inclusion of etoposide in 12 pts (25%), anthracyclines in 9 (19%) & platinum agents in 3 pts (6%). The overall response to 1st line therapy was 40% (19% complete response) with stable disease in 10%, progression in 35% & unknown in 15%. Seven pts (15%) received consolidative stem cell transplantation (SCT), which was allogeneic in all but 1 case. The 2-year PFS for the 48 bona fide pts was 39% (95% CI 0.26-0.59) (Fig 1A) & 2-year OS was 36% (95% CI 0.23-.56) (Fig 1B). The 26 cases in the 2nd tier had overall similar 2-year PFS of 41% (95% CI 0.15-67) and OS of 37% (95% CI 0.22-0.62). In terms of impact of therapy, use of consolidative SCT in 1st remission was associated with improved survival (P=0.02) (Fig 1C). No other therapeutic variable had significance. In UVA for baseline factors, PS (P=0.006) (Fig 1D) and increased vs. normal LDH (P=0.05) were significantly associated with OS. Median OS for pts with normal LDH was 25 months vs 12 months with increased LDH. Median OS for pts with ECOG PS 0 was not reached vs approximately 14 months for ECOG PS 1-3. Conclusions: To the best of our knowledge, this series represents one of the largest reported to date of PCGDTCL. Accurate diagnosis and classification of PCGDTCL need ongoing analysis and delineation. Using strict criteria, only 60% of cases across 10 academic centers were confirmed as bona fide PCGDTCL. Analysis of these pts treated in the modern era demonstrated modest survival. In addition, we identified several prognostic factors, in particular LDH and ECOG PS, associated with patient outcome. Furthermore, the incorporation of allogeneic SCT in 1st remission may contribute to improved long-term survival. Enhanced treatment options and continued collaboration are critically needed in this rare disease. Disclosures Bennani: Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board. Landsburg:Takeda: Research Funding; Takeda: Research Funding; Triphase: Research Funding; Seattle Genetics: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Triphase: Research Funding; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Speakers Bureau; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Haun:Karger, Inc.: Other: Royalties: Textbook. William:Techspert: Consultancy; Guidepoint Global: Consultancy; Defined Health: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy. Mehta-Shah:Kiowa Hakka Kirin: Consultancy; Celgene: Research Funding; Roche/Genentech: Research Funding; Bristol Myers Squibb: Research Funding; Verastem Pharmaceuticals: Research Funding; Innate Pharmaceuticals: Research Funding. Wilcox:Bristol-Myers Squibb: Research Funding; Millenium/Takeda: Research Funding; CTI Biopharma: Research Funding; Incyte: Research Funding. Feldman:AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Pfizer: Research Funding; Portola Pharma: Research Funding; Roche: Research Funding; Trillium: Research Funding; Viracta: Research Funding; Roche: Research Funding; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Cell Medica: Research Funding; Amgen: Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Corvus: Research Funding. Evens:Tesaro: Research Funding; Pharmacyclics: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding. Horwitz:Affimed: Consultancy; Mundipharma: Consultancy; Forty-Seven: Research Funding; Astex: Consultancy; Aileron: Research Funding; Kyowa Hakko Kirin: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Mundipharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Trillium: Research Funding; Forty-Seven: Research Funding; Trillium: Research Funding; Portola: Consultancy; Kura: Consultancy; Celgene: Consultancy, Research Funding; Astex: Consultancy; Kyowa Hakko Kirin: Consultancy; Aileron: Research Funding; Portola: Consultancy; Kura: Consultancy; Kura: Consultancy; Miragen: Consultancy; Miragen: Consultancy; Portola: Consultancy; Innate Pharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Mundipharma: Consultancy; ADCT Therapeutics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; Forty-Seven: Research Funding; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Celgene: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADCT Therapeutics: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Affimed: Consultancy; Innate Pharma: Consultancy; Affimed: Consultancy; Astex: Consultancy; Trillium: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty-Seven: Research Funding; Mundipharma: Consultancy; Astex: Consultancy; Celgene: Consultancy, Research Funding; Innate Pharma: Consultancy; Kura: Consultancy; ADCT Therapeutics: Research Funding; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Miragen: Consultancy; Portola: Consultancy; Aileron: Research Funding; Kyowa Hakko Kirin: Consultancy; Affimed: Consultancy; Trillium: Research Funding; Millennium/Takeda: Consultancy, Research Funding.

Abstract: Background: The genetic basis and the genome-wide abnormalities underlying most forms of cancer are being comprehensively annotated in many human malignancies. However, the contribution of epigenetic aberrations, particularly the post-translational modifications (PTM) of histone tails has not been investigated. This is largely due to lack of approaches to comprehensively interrogate the status of the numerous PTMs that define histone marks which control gene expression and complex biologic processes such as cancer. Sézary Syndrome (SS) is an aggressive form of cutaneous T-cell lymphoma (CTCL) characterized by poor outcomes and complex genetic alterations frequently targeting epigenetic regulators and chromatin remodelers. CTCLs represent the first FDA-approved disease for treatment using histone deacetylase inhibitors (HDACi) such as romidepsin, but the direct consequences of this treatment on histone PTMs remain unknown. Here we define the histone PTM signatures of CTCL/SS by using a novel unbiased strategy leveraging tandem mass spectrometry (MS/MS)-based quantitative proteomics to study the comprehensive combinatorial histone PTM code in a cohort of primary SS samples, and 4 CTCL/SS cell lines in comparison with normal reactive CD4+ T-lymphocytes from healthy individuals. Methods: CD4+ T-cells were isolated using CD4 immunomagnetic beads from PBMC's of healthy volunteers (n=8) or patients with diagnosed SS (n=20). CD4+ cells were frozen and subsequently analyzed in batches. The CTCL/SS-derived cell lines (HH and MJ, HuT78 and H9) were also analyzed each with three biological replicates. Histones were acid extracted from isolated nuclei. Total bulk histones were propionylated and trypsinized prior to MS analysis. Nano-scale liquid chromatography followed by -tandem mass spectrometry (nano LC-MS/MS) data acquisition was performed in an Orbitrap FusionTM TribridTM MS in technical triplicates for each sample with a data-independent acquisition (DIA)-method using a 50 m/z quadrupole-isolation windows that steps across the 200-1500 m/z ranges. Data analysis was performed using EpiProfile for single and combinatorial histone PTM analysis and quantification. Orthogonal validation for selected modifications was performed using western blotting and single-cell mass cytometry by time of flight (CyTOF) analysis. Results: Our quantitative epiproteomic strategy interrogated the relative ratios of a total of 228 histone PTM combinations, and 20 histone variants in a well-characterized cohort of SS patient samples, four CTCL cell lines and a cohort of normal primary CD4+ T-lymphocytes isolated from healthy individuals. With this approach, we were able to identify and quantify 23 unique histone peptides on histone H4, 105 on histone H3, 80 on histone H2A, 12 on histone H2B and 28 on histone H1 across every sample. Pearson correlation and principal component analysis of overall histone PTMs profiles across all samples provided accurate discrimination. We found a distinct pattern of histone PTMs in both SS patient samples and CTCL cell lines that were strikingly different from CD4+ T-cells obtained from healthy individuals. Notably, differences between cell lines and primary patient samples are more marked than those within individual SS primary patient samples, implying that cell lines may poorly recapitulate some aspects of in vivo biology. Unsupervised hierarchical clustering of the primary patient samples, cell lines and the normal CD4+ T-cells performed based on abundances of the identified histone PTMs revealed disease-specific ubiquitous marks as well as disease-specific unique marks for SS. Among the analyzed histone PTMs, H3K27ac, H3.3K27ac, H4K8ac, H4K20ac, H3K4me3, H3K18me1, H3K79me3 and H4K20me3 were distinct between healthy and CTCL CD4+ T-cells. Selected differential marks such as H4K20me3 were orthogonally corroborated by Western blotting and CyTOF mass cytometry analysis. Conclusions: For the first time, we have defined the histone code of CTCL/SS using global mass spectrometry based quantitative proteomics with high specificity and sensitivity. The results of our MS-based epiproteomic profiling revealed disease-specific histone PTM signatures and opportunities to exploit tractable changes induced by HDACi treatment as clinically actionable molecular biomarkers and therapeutic targets. Disclosures No relevant conflicts of interest to declare.

Abstract: Self‐determination theory suggests that satisfaction of an individual's basic psychological needs (for competence, autonomy, and relatedness) is a key for well‐being. This has gained empirical support in multiple life domains, but little is known about the way that need satisfaction interacts between work and home. Drawing from ideas of work–home compensation, we expect that the benefits of need satisfaction in the home domain are reduced when needs are satisfied in the work domain. We tested this hypothesis with a daily diary study involving 91 workers. Results showed that individuals particularly benefit from satisfaction of their need for competence in the home domain when it is not satisfied during the working day. No such interactions were found between the needs for autonomy or relatedness. Our study highlights that the interaction of need satisfaction across domains represents a boundary condition for the beneficial effects of need satisfaction. Practitioner points The study examines the interplay between daily need satisfaction at work and at home and its relation to employee well‐being at bedtime. Employees particularly benefit from competence need satisfaction at home (e.g., doing a hobby which challenges them) on days when they do not get a sense of competence from their job (e.g., if the tasks are not particularly challenging, or they are underperforming).