Showing papers by "University of Kiel published in 2011"

Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation

Abstract: At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects. Conclusions Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann–La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.)

Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma

Abstract: A B S T R AC T Background Ipilimumab monotherapy (at a dose of 3 mg per kilogram of body weight), as compared with glycoprotein 100, improved overall survival in a phase 3 study involving patients with previously treated metastatic melanoma. We conducted a phase 3 study of ipilimumab (10 mg per kilogram) plus dacarbazine in patients with previously untreated metastatic melanoma. Methods We randomly assigned 502 patients with previously untreated metastatic melanoma, in a 1:1 ratio, to ipilimumab (10 mg per kilogram) plus dacarbazine (850 mg per square meter of body-surface area) or dacarbazine (850 mg per square meter) plus placebo, given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through week 22. Patients with stable disease or an objective response and no doselimiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary end point was overall survival. Results Overall survival was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months vs. 9.1 months, with higher survival rates in the ipilimumab–dacarbazine group at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%) (hazard ratio for death, 0.72; P<0.001). Grade 3 or 4 adverse events occurred in 56.3% of patients treated with ipilimumab plus dacarbazine, as compared with 27.5% treated with dacarbazine and placebo (P<0.001). No drug-related deaths or gastrointestinal perforations occurred in the ipilimumab–dacarbazine group. Conclusions Ipilimumab (at a dose of 10 mg per kilogram) in combination with dacarbazine, as compared with dacarbazine plus placebo, improved overall survival in patients with previously untreated metastatic melanoma. The types of adverse events were consistent with those seen in prior studies of ipilimumab; however, the rates of elevated liver-function values were higher and the rates of gastrointestinal events were lower than expected on the basis of prior studies. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00324155.)

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Abstract: Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.

Abstract: We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10−5. We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10−17; including ADGC data, meta P = 5.0 × 10−21) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10−14; including ADGC data, meta P = 1.2 × 10−16) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10−4; including ADGC data, meta P = 8.6 × 10−9), CD33 (GERAD+, P = 2.2 × 10−4; including ADGC data, meta P = 1.6 × 10−9) and EPHA1 (GERAD+, P = 3.4 × 10−4; including ADGC data, meta P = 6.0 × 10−10).

Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease

Abstract: We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 - 10'8 and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.

Spontaneous atomic-scale magnetic skyrmion lattice in two dimensions

Abstract: Skyrmions are topologically protected field configurations with particle-like properties that play an important role in various fields of science. Recently, skyrmions have been observed to be stabilized by an external magnetic field in bulk magnets. Here, we describe a two-dimensional square lattice of skyrmions on the atomic length scale as the magnetic ground state of a hexagonal Fe film of one-atomic-layer thickness on the Ir(111) surface. Using spin-polarized scanning tunnelling microscopy we can directly image this non-collinear spin texture in real space on the atomic scale and demonstrate that it is incommensurate to the underlying atomic lattice. With the aid of first-principles calculations, we develop a spin model on a discrete lattice that identifies the interplay of Heisenberg exchange, the four-spin and the Dzyaloshinskii-Moriya interaction as the microscopic origin of this magnetic state.

Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.

Abstract: Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.

Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors

Abstract: CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.

Deep Brain Stimulation for Parkinson Disease: An Expert Consensus and Review of Key Issues

Abstract: Objective: To provide recommendations to patients, physicians, and other health care providers on several issues involving deep brain stimulation (DBS) for Parkinson disease (PD). Data Sources and Study Selection: An international consortium of experts organized, reviewed the literature, and attended the workshop. Topics were introduced at the workshop, followed by group discussion. Data Extraction and Synthesis: A draft of a consensus statement was presented and further edited after plenary debate. The final statements were agreed on by all members. Conclusions: (1) Patients with PD without significant active cognitive or psychiatric problems who have medically intractable motor fluctuations, intractable tremor, or intolerance of medication adverse effects are good candidates for DBS. (2) Deep brain stimulation surgery is best performed by an experienced neurosurgeon with expertise in stereotactic neurosurgery who is working as part of a interprofessional team. (3) Surgical complication rates are extremely variable, with infection being the most commonly reported complication of DBS. (4) Deep brain stimulation programming is best accomplished by a highly trained clinician and can take 3 to 6 months to obtain optimal results. (5) Deep brain stimulation improves levodopa-responsive symptoms, dyskinesia, and tremor; benefits seem to be long-lasting in many motor domains. (6) Subthalamic nuclei DBS may be complicated by increased depression, apathy, impulsivity, worsened verbal fluency, and executive dysfunction in a subset of patients. (7) Both globus pallidus pars interna and subthalamic nuclei DBS have been shown to be effective in addressing the motor symptoms of PD. (8) Ablative therapy is still an effective alternative and should be considered in a select group of appropriate patients. Arch Neurol. 2011; 68(2):165-171. Published online October 11, 2010. doi:10.1001/archneurol.2010.260

Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial

Abstract: Objective The aim of this study was to assess the efficacy and safety of adalimumab (ADA), a recombinant human monoclonal antibody against tumour necrosis factor a (TNF), for the induction of clinical remission in anti-TNF nao¨ve patients with moderately to severely active ulcerative colitis. Methods This 8-week, multicentre, randomised, doubleblind, placebo-controlled study (NCT00385736), conducted at 94 centres in North America and Europe, enrolled ambulatory adult patients with Mayo score of $6 points and endoscopic subscore of $2 points despite treatment with corticosteroids and/or immunosuppressants. Under the original study protocol, 186 patients were randomised (1:1) to subcutaneous treatment with ADA160/80 (160 mg at week 0, 80 mg at week 2, 40 mg at weeks 4 and 6) or placebo. Subsequently, at the request of European regulatory authorities, the protocol was amended to include a second induction group (ADA80/40: 80 mg at week 0, 40 mg at weeks 2, 4 and 6). The primary efficacy endpoint was clinical remission (Mayo score #2 with no individual subscore >1) at week 8, assessed in 390 patients randomised (1:1:1) to ADA160/80, ADA80/40, or placebo. Safety was assessed in all enrolled patients. Patients, study site personnel, investigators, and the sponsor were blinded to treatment assignment. Results At week 8, 18.5% of patients in the ADA160/80 group (p¼0.031 vs placebo) and 10.0% in the ADA80/40 group (p¼0.833 vs placebo) were in remission, compared with 9.2% in the placebo group. Serious adverse events occurred in 7.6%, 3.8% and 4.0% of patients in the placebo, ADA80/40, and ADA160/80 groups, respectively. There were two malignancies in the placebo group, none in the ADA groups. There were no cases of tuberculosis and no deaths. Conclusions ADA160/80 was safe and effective for induction of clinical remission in patients with moderately to severely active ulcerative colitis failing treatment with corticosteroids and/or immunosuppressants. Clinical trial NCT00385736.

On the origin of charge-density waves in select layered transition-metal dichalcogenides.

Abstract: The occurrence of charge-density waves in three selected layered transition-metal dichalcogenides-1T-TaS(2), 2H-TaSe(2) and 1T-TiSe(2)-is discussed from an experimentalist's point of view with a particular focus on the implications of recent angle-resolved photoelectron spectroscopy results. The basic models behind charge-density-wave formation in low-dimensional solids are recapitulated, the experimental and theoretical results for the three selected compounds are reviewed, and their band structures and spectral weight distributions in the commensurate charge-density-wave phases are calculated using an empirical tight-binding model. It is explored whether the origin of charge-density waves in the layered transition-metal dichalcogenides can be understood in a unified way on the basis of a few measured and calculated parameters characterizing the interacting electron-lattice system. It is found that the predictions of the standard mean-field model agree only semi-quantitatively with the experimental data and that there is not one generally dominant factor driving charge-density-wave formation in this family of layer compounds. The need for further experimental and theoretical scrutiny is emphasized.

In Vivo Anomalous Diffusion and Weak Ergodicity Breaking of Lipid Granules

Abstract: Combining extensive single particle tracking microscopy data of endogenous lipid granules in living fission yeast cells with analytical results we show evidence for anomalous diffusion and weak ergodicity breaking. Namely we demonstrate that at short times the granules perform subdiffusion according to the laws of continuous time random walk theory. The associated violation of ergodicity leads to a characteristic turnover between two scaling regimes of the time averaged mean squared displacement. At longer times the granule motion is consistent with fractional Brownian motion.

Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data

Abstract: Objective To use genetic variants as unconfounded proxies of C reactive protein concentration to study its causal role in coronary heart disease. Design Mendelian randomisation meta-analysis of ind ...

Species-specific responses of Late Quaternary megafauna to climate and humans

Abstract: Despite decades of research, the roles of climate and humans in driving the dramatic extinctions of large-bodied mammals during the Late Quaternary period remain contentious. Here we use ancient DNA, species distribution models and the human fossil record to elucidate how climate and humans shaped the demographic history of woolly rhinoceros, woolly mammoth, wild horse, reindeer, bison and musk ox. We show that climate has been a major driver of population change over the past 50,000 years. However, each species responds differently to the effects of climatic shifts, habitat redistribution and human encroachment. Although climate change alone can explain the extinction of some species, such as Eurasian musk ox and woolly rhinoceros, a combination of climatic and anthropogenic effects appears to be responsible for the extinction of others, including Eurasian steppe bison and wild horse. We find no genetic signature or any distinctive range dynamics distinguishing extinct from surviving species, emphasizing the challenges associated with predicting future responses of extant mammals to climate and human-mediated habitat change.

Filter-Based Active Damping of Voltage Source Converters With $LCL$ Filter

Abstract: Pulsewidth modulation (PWM) voltage source converters are becoming a popular interface to the power grid for many applications. Hence, issues related to the reduction of PWM harmonics injection in the power grid are becoming more relevant. The use of high-order filters like LCL filters is a standard solution to provide the proper attenuation of PWM carrier and sideband voltage harmonics. However, those grid filters introduce potentially unstable dynamics that should be properly damped either passively or actively. The second solution suffers from control and system complexity (a high number of sensors and a high-order controller), even if it is more attractive due to the absence of losses in the damping resistors and due to its flexibility. An interesting and straightforward active damping solution consists in plugging in, in cascade to the main controller, a filter that should damp the unstable dynamics. No more sensors are needed, but there are open issues such as preserving the bandwidth, robustness, and limited complexity. This paper provides a systematic approach to the design of filter-based active damping methods. The tuning procedures, performance, robustness, and limitations of the different solutions are discussed with theoretical analysis, selected simulation, and experimental results.

Crystal chemistry and stability of "Li7La3Zr2O12" garnet: a fast lithium-ion conductor

Abstract: Recent research has shown that certain Li-oxide garnets with high mechanical, thermal, chemical, and electrochemical stability are excellent fast Li-ion conductors. However, the detailed crystal chemistry of Li-oxide garnets is not well understood, nor is the relationship between crystal chemistry and conduction behavior. An investigation was undertaken to understand the crystal chemical and structural properties, as well as the stability relations, of Li7La3Zr2O12 garnet, which is the best conducting Li-oxide garnet discovered to date. Two different sintering methods produced Li-oxide garnet but with slightly different compositions and different grain sizes. The first sintering method, involving ceramic crucibles in initial synthesis steps and later sealed Pt capsules, produced single crystals up to roughly 100 μm in size. Electron microprobe and laser ablation inductively coupled plasma mass spectrometry (ICP-MS) measurements show small amounts of Al in the garnet, probably originating from the crucible...

Structure and dynamics of the fast lithium ion conductor “Li7La3Zr2O12”

Abstract: The solid lithium-ion electrolyte “Li7La3Zr2O12” (LLZO) with a garnet-type structure has been prepared in the cubic and tetragonal modification following conventional ceramic syntheses routes. Without aluminium doping tetragonal LLZO was obtained, which shows a two orders of magnitude lower room temperature conductivity than the cubic modification. Small concentrations of Al in the order of 1 wt% were sufficient to stabilize the cubic phase, which is known as a fast lithium-ion conductor. The structure and ion dynamics of Al-doped cubic LLZO were studied by impedance spectroscopy, dc conductivity measurements, 6Li and 7Li NMR, XRD, neutron powder diffraction, and TEM precession electron diffraction. From the results we conclude that aluminium is incorporated in the garnet lattice on the tetrahedral 24dLi site, thus stabilizing the cubic LLZO modification. Simulations based on diffraction data show that even at the low temperature of 4 K the Li ions are blurred over various crystallographic sites. This strong Li ion disorder in cubic Al-stabilized LLZO contributes to the high conductivity observed. The Li jump rates and the activation energy probed by NMR are in very good agreement with the transport parameters obtained from electrical conductivity measurements. The activation energy Ea characterizing long-range ion transport in the Al-stabilized cubic LLZO amounts to 0.34 eV. Total electric conductivities determined by ac impedance and a four point dc technique also agree very well and range from 1 × 10−4 Scm−1 to 4 × 10−4 Scm−1 depending on the Al content of the samples. The room temperature conductivity of Al-free tetragonal LLZO is about two orders of magnitude lower (2 × 10−6 Scm−1, Ea = 0.49 eV activation energy). The electronic partial conductivity of cubic LLZO was measured using the Hebb–Wagner polarization technique. The electronic transference number te− is of the order of 10−7. Thus, cubic LLZO is an almost exclusive lithium ion conductor at ambient temperature.

Development of the Crohn's disease digestive damage score, the Lémann score†‡§

Abstract: Crohn's disease (CD) is a chronic progressive destructive disease. Currently available instruments measure disease activity at a specific point in time. An instrument to measure cumulative structural damage to the bowel, which may predict long-term disability, is needed. The aim of this article is to outline the methods to develop an instrument that can measure cumulative bowel damage. The project is being conducted by the International Program to develop New Indexes in Crohn's disease (IPNIC) group. This instrument, called the Crohn's Disease Digestive Damage Score (the Lemann score), should take into account damage location, severity, extent, progression, and reversibility, as measured by diagnostic imaging modalities and the history of surgical resection. It should not be "diagnostic modality driven": for each lesion and location, a modality appropriate for the anatomic site (for example: computed tomography or magnetic resonance imaging enterography, and colonoscopy) will be used. A total of 24 centers from 15 countries will be involved in a cross-sectional study, which will include up to 240 patients with stratification according to disease location and duration. At least 120 additional patients will be included in the study to validate the score. The Lemann score is expected to be able to portray a patient's disease course on a double-axis graph, with time as the x-axis, bowel damage severity as the y-axis, and the slope of the line connecting data points as a measure of disease progression. This instrument could be used to assess the effect of various medical therapies on the progression of bowel damage.

L-asparaginase treatment in acute lymphoblastic leukemia: a focus on Erwinia asparaginase

Abstract: Asparaginases are a cornerstone of treatment protocols for acute lymphoblastic leukemia (ALL) and are used for remission induction and intensification treatment in all pediatric regimens and in the majority of adult treatment protocols. Extensive clinical data have shown that intensive asparaginase treatment improves clinical outcomes in childhood ALL. Three asparaginase preparations are available: the native asparaginase derived from Escherichia coli (E. coli asparaginase), a pegylated form of this enzyme (PEG-asparaginase), and a product isolated from Erwinia chrysanthemi, ie, Erwinia asparaginase. Clinical hypersensitivity reactions and silent inactivation due to antibodies against E. coli asparaginase, lead to inactivation of E. coli asparaginase in up to 60% of cases. Current treatment protocols include E. coli asparaginase or PEG-asparaginase for first-line treatment of ALL. Typically, patients exhibiting sensitivity to one formulation of asparaginase are switched to another to ensure they receive the most efficacious treatment regimen possible. Erwinia asparaginase is used as a second- or third-line treatment in European and US protocols. Despite the universal inclusion of asparaginase in such treatment protocols, debate on the optimal formulation and dosage of these agents continues. This article provides an overview of available evidence for optimal use of Erwinia asparaginase in the treatment of ALL.

Design of a perfect black absorber at visible frequencies using plasmonic metamaterials.

Abstract: The design and fabrication of a plasmonic black absorber with almost 100% absorbance spanning a broad range of frequencies from ultraviolet (UV) to the near infrared (NIR) is demonstrated. The perfect plasmonic absorber is achieved by a combination of a metal film with suitable metal/dielectric nanocomposites. Our fabrication technique is simple, versatile, cost-effective, and compatible with current industrial methods for solar absorber production.

Magnetic bistability of molecules in homogeneous solution at room temperature.

Abstract: Magnetic bistability, as manifested in the magnetization of ferromagnetic materials or spin crossover in transition metal complexes, has essentially been restricted to either bulk materials or to very low temperatures. We now present a molecular spin switch that is bistable at room temperature in homogeneous solution. Irradiation of a carefully designed nickel complex with blue-green light (500 nanometers) induces coordination of a tethered pyridine ligand and concomitant electronic rearrangement from a diamagnetic to a paramagnetic state in up to 75% of the ensemble. The process is fully reversible on irradiation with violet-blue light (435 nanometers). No fatigue or degradation is observed after several thousand cycles at room temperature under air. Preliminary data show promise for applications in magnetic resonance imaging.

Reduction of disulphide bonds unmasks potent antimicrobial activity of human β-defensin 1

Abstract: Human epithelia are permanently challenged by bacteria and fungi, including commensal and pathogenic microbiota. In the gut, the fraction of strict anaerobes increases from proximal to distal, reac ...

New gene functions in megakaryopoiesis and platelet formation

Abstract: Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.