In eukaryotes, Suv39h H3K9 trimethyltransferases are required for pericentric heterochromatin formation and function. In early mouse preimplantation embryos, however, paternal pericentric heterochromatin lacks Suv39h-mediated H3K9me3 and downstream marks. Here we demonstrate Ezh2-independent targeting of maternally provided polycomb repressive complex 1 (PRC1) components to paternal heterochromatin. In Suv39h2 maternally deficient zygotes, PRC1 also associates with maternal heterochromatin lacking H3K9me3, thereby revealing hierarchy between repressive pathways. In Rnf2 maternally deficient zygotes, the PRC1 complex is disrupted, and levels of pericentric major satellite transcripts are increased at the paternal but not the maternal genome. We conclude that in early embryos, Suv39h-mediated H3K9me3 constitutes the dominant maternal transgenerational signal for pericentric heterochromatin formation. In absence of this signal, PRC1 functions as the default repressive back-up mechanism. Parental epigenetic asymmetry, also observed along cleavage chromosomes, is resolved by the end of the 8-cell stage--concurrent with blastomere polarization--marking the end of the maternal-to-embryonic transition.

Consideration of less corneal thinning favours A-CXL, whereas the deeper demarcation line and greater changes in minimum keratometric values in C-CXL may indicate a higher treatment efficacy. Altogether, C-CXL, as well as A-CXL, provides successful results in the strengthening of corneal tissue.

The most accurate predictions of actual postoperative refraction were achieved using the Barrett Universal II, Hill-RBF, Olsen, or T2 formula. Thus, one of these formulas should be used for IOL power calculation of the quadrifocal IOL.

Purpose: To compare the efficacy and safety of femtosecond laser–assisted cataract surgery (FLACS) with conventional cataract surgery (CCS). Setting: Department of Ophthalmology, Goethe-University, Frankfurt am Main, Germany. Design: Meta-analysis. Methods: PubMed, Cochrane Library, and EMBASE were systematically searched for studies comparing FLACS and CCS. Outcomes were efficacy and safety parameters. The effect measures were weighted mean differences or odds ratios with 95% CIs. Results: A total of 73 studies (25 randomized controlled, 48 observational) were reviewed with a total of 12 769 eyes treated with FLACS and 12 274 eyes treated with CCS. In eyes treated with FLACS, uncorrected and corrected distance visual acuities and spherical equivalent after 1 month to 3 months (P = .04, P = .005, and P = .007, respectively) were better, total and effective phacoemulsification times were shorter (P < .001 each), cumulative dissipated energy was less (P < .001), circularity was more accurate (P < .001), central corneal thickness after 1 day and 1 month to 3 months was less (P < .001 and P = .004, respectively), and endothelial cell loss after 3 to 6 weeks and 3 months was less (P = .002 and P < .001, respectively) compared with CCS. Anterior capsule ruptures occurred more often with FLACS. No significant differences among groups were found in visual acuity at 1 week and after 6 months or in posterior capsule rupture rates and endothelial cell loss after 6 months. Conclusions: Both FLACS and CCS are effective and safe. FLACS required less ultrasound energy and a more precise treatment. However, mid-term visual acuity did not show any difference between both methods.

Cancer heterogeneity at the proteome level may explain differences in therapy response and prognosis beyond the currently established genomic and transcriptomic-based diagnostics. The relevance of proteomics for disease classifications remains to be established in clinically heterogeneous cancer entities such as chronic lymphocytic leukemia (CLL). Here, we characterize the proteome and transcriptome alongside genetic and ex-vivo drug response profiling in a clinically annotated CLL discovery cohort (n = 68). Unsupervised clustering of the proteome data reveals six subgroups. Five of these proteomic groups are associated with genetic features, while one group is only detectable at the proteome level. This new group is characterized by accelerated disease progression, high spliceosomal protein abundances associated with aberrant splicing, and low B cell receptor signaling protein abundances (ASB-CLL). Classifiers developed to identify ASB-CLL based on its characteristic proteome or splicing signature in two independent cohorts (n = 165, n = 169) confirm that ASB-CLL comprises about 20% of CLL patients. The inferior overall survival in ASB-CLL is also independent of both TP53- and IGHV mutation status. Our multi-omics analysis refines the classification of CLL and highlights the potential of proteomics to improve cancer patient stratification beyond genetic and transcriptomic profiling.

Background: The treatment of patients with metastatic melanomas that harbour BRAF V600E or V600K mutations with trametinib plus dabrafenib appears to be superior to treatment with vemurafenib alone. This treatment regimen is likely to become available in Switzerland in the near future. Objectives: To determine the cost-effectiveness of trametinib plus dabrafenib. Methods: A Markov cohort simulation was conducted to model the clinical course of typical patients with metastatic melanoma. Information on response rates, clinical condition and follow-up treatments were derived and transition probabilities estimated based on the results of a clinical trial that compared treatment with trametinib plus dabrafenib vs. vemurafenib alone. Results: Treatment with trametinib plus dabrafenib was estimated to cost an additional CHF199 647 (Swiss francs) on average and yield a gain of 0·52 qualityadjusted life years (QALYs), resulting in an incremental cost-effectiveness ratio of CHF385 603 per QALY. Probabilistic sensitivity analyses showed that a willingness-to-pay threshold of CHF100 000 per QALY would not be reached at the current US price of trametinib. Conclusions: The introduction of trametinib in Switzerland at US market prices for the treatment of metastatic BRAF V600-mutated melanoma with trametinib plus dabrafenib is unlikely to be cost-effective compared with vemurafenib monotherapy. A reduction in the total price of the combination therapy is required to achieve an acceptable cost-effectiveness ratio for this clinically promising treatment. Accepted ArticleThis article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/bjd.14152 This article is protected by copyright. All rights reserved. What is known about this topic?• Several new promising treatments for patients with metastatic melanoma that harbour BRAF V600E or V600K mutations have recently become available • Trametinib is not yet available in Switzerland, but approval is expected in 2015 • These new treatments are very expensive Accepted ArticleThis article is protected by copyright. All rights reserved. What does this study add?• Although clinically promising, at current US trametinib prices, trametinib plus dabrafenib will not be cost effective compared to vemurafenib in the Swiss setting • Only a reduction in the price of the combination therapy would make this therapy cost effective AbstractBackground and Objective: The treatment of patients with metastatic melanomas that harbour BRAF

BCL-2 inhibition has been shown to be effective in acute myeloid leukemia (AML) in combination with hypomethylating agents or low-dose cytarabine. However, resistance and relapse represent major clinical challenges. Thus, there is an unmet need to overcome resistance to current venetoclax-based strategies. We performed high-throughput drug screening to identify effective combination partners for venetoclax in AML. Overall, 64 anti-leukemic drugs were screened in 31 primary high-risk AML samples with or without venetoclax. Gilteritinib exhibited highest synergy with venetoclax in FLT3 wildtype AML. The combination of gilteritinib and venetoclax increased apoptosis, reduced viability, and was active in venetoclax-azacitidine resistant cell lines and primary patient samples. Proteomics revealed increased FLT3 wildtype signaling in specimens with low in-vitro response to the currently used venetoclax-azacitidine combination. Mechanistically, venetoclax with gilteritinib decreased phosphorylation of ERK and GSK3B via combined AXL and FLT3 inhibition with subsequent suppression of the antiapoptotic protein MCL-1. MCL-1 downregulation was associated with increased MCL-1 phosphorylation of serine 159, decreased phosphorylation of threonine 161 and proteasomal degradation. Gilteritinib and venetoclax were active in a FLT3 wildtype AML PDX model with TP53 mutation and reduced leukemic burden in four FLT3 wildtype AML patients receiving venetoclax-gilteritinib off-label after developing refractory disease under venetoclax-azacitidine. In summary, our results suggest that combined inhibition of FLT3/AXL potentiates venetoclax response in FLT3-wildtype AML by inducing MCL-1 degradation. Thus, the venetoclax-gilteritinib combination merits testing as potentially active regimen in high-risk AML patients with FLT3 wildtype.

Cancer heterogeneity at the proteome level may explain differences in therapy response and prognosis beyond the currently established genomic and transcriptomic based diagnostics. The relevance of proteomics for disease classifications remains to be established in clinically heterogeneous cancer entities such as chronic lymphocytic leukemia (CLL). Here, we characterized the proteome and transcriptome in-depth alongside genetic and ex-vivo drug response profiling in a clinically well annotated CLL discovery cohort (n= 68). Unsupervised clustering of the proteome data revealed six subgroups. Five of these proteomic groups were associated with genetic features, while one group was only detectable at the proteome level. This new group was characterized by accelerated disease progression, high spliceosomal protein abundances associated with aberrant splicing, and low B cell receptor signaling protein abundances (ASB-CLL). We developed classifiers to identify ASB-CLL based on its characteristic proteome or splicing signature in two independent cohorts (n= 165, n= 169) and confirmed that ASB-CLL comprises about 20 % of CLL patients. The inferior overall survival observed in ASB-CLL was independent of both TP53- and IGHV mutation status. Our multi-omics analysis refines the classification of CLL and highlights the potential of proteomics to improve cancer patient stratification beyond genetic and transcriptomic profiling.