Heterogeneous genetic background of Hungarian patients with pheochromocytoma/paraganglioma requires gene panel testing

Introduction Pheochromocytomas and paragangliomas (Pheo/PGL) are rare neuroendocrine tumours arising from the adrenal medulla or the symphathetic paraganglia, respectively. Germline mutations are present in w40% of the patients. To date, at least 16 genes have been demonstrated to be involved in the genetic background of Pheo/PGL. Prioritization in order of genes tested can be applied, but if the probability of a disease-associated germline mutation exceeds 10% the testing of all susceptibility genes is recommended. Using next generation sequencing (NGS) based methods for genetic testing of Pheo/PGL associated genes progressively becomes part of the routine diagnostics. Objective To assess the genetic background of Hungarian patients with Pheo/PGL and to develop a NGS based gene panel assay for analysis of Pheo/PGL susceptibility genes. Methods We examined 131 patients with the diagnosis of Pheo/PGL diagnosed and nursed at the 2nd Department of Medicine, Semmelweis University. The prevalence of the germline mutations of Pheo/PGL genes was determined using conventional methods. Genotype-phenotype correlations were evaluated. A gene panel covering 15 genes (RET, VHL, NF1, EPAS, EGLN1, KIF1B, SDHA, SDHB, SDHAF2, SDHC, SDHD, FH, MAX, TMEM127, MEN1) was developed and analytical sensitivity was evaluated on 36 patients with known genetic background. Library preparation was performed using SeqCapEZ capture platform with our probe design. Illumina MiSeq instrument was used for sequencing. Sequencing data were analysed with GATK workflow. Variant annotation was performed with SNPeffect. Results Germline mutations of Pheo/PGL genes were present in at 34% of the patients: 10 (7.6%) SDHB, 9 (6.9%) RET, 5 (3.8%) VHL, TMEM127, MDH2, 4 (3%) NF1, 3 (2.3%) SDHD, 2 (1.5%) SDHC and KIF1B. 5 of 10 SDHB mutation carriers developed malignant disease. Homozygous form of a MDH2 variant was associated with malignancy. Among the 10 patients with bilateral adrenal Pheo 4 RET, 2 TMEM127 and 1 VHL mutations were identified. The coverage of genes in our panel was higher than 150 reads in all regions and all known mutations were correctly identified. Discussion Our findings regarding the prevalence of germline mutations in the development of Pheo/PGL are in accordance with the literature. No founder mutation occurred in our population as we could detect mutations in 9 genes, underlining the need of novel methods for mutation analysis in everyday clinical practice. Our NGSbased gene panel performed accurately, however two recently identified genes (MDH2, GOT2) were not covered

Next generation sequencing for characterization of mitochondrial genome in pituitary adenomas

Introduction Disrupted mitochondrial functions and genetic variations of mitochondrial DNA (mtDNA) have been observed in different tumors. Regarding pituitary adenomas mtDNA was evaluated only in oncocytic type using PCR based methods and it showed high prevalence of Complex I variants. Next generation sequencing (NGS) allows high throughput sequencing and it is useful for accurate identification of heteroplasmy of mitochondrial genome as well. Aim We aimed to investigate the entire mitochondrial genome in different adenoma types. Material and methods We collected 22 gonadotroph (GO), 11 growth hormone producing (GH) and 11 null-cell (NC) adenoma specimens from samples removed by transsphenoidal surgery. From fresh frozen tissues DNA extraction was performed using QIAamp Fast DNA Tissue Kit. For library preparation VariantPro™ Amplicon Mitochondrion Panel kit was used. The total mtDNA (16569 bp) was sequenced on Illumina MiSeq Instrument. Following complex bioinformatic analysis Revised Cambridge Reference Sequence (rCRS) of the human mitochondrial DNA was used as reference. Heteroplasmy was determined using 3% cutoff. Results. The whole mitochondrial genome were covered by 630±370 (avg±SE) reads per base. 496 variants were identified in adenomas compared to reference sequence. Overall a low (7.22%) heteroplasmy prevalence was found. Based on mitochondrial sequence variants by hierarchical cluster analysis we could not discriminate different adenoma types. No association between Ki-67 index or recurrent-nonrecurrent status of adenomas and mitochondrial variants were detected. Four variants appeared more often in null-cell adenomas compared to gonadotroph adenomas (chrM_188: 18% vs. 0%, chrM_16093: 18% vs. 0%, chrM_185: 27% vs. 0% and chrM_14798: 36% vs. 5%; Padj=0.0246, 0.0246, 0.01542 and 0.01829, respectively). Of these variants chrM_14798, chrM_4216 and chrM_15452 are non-synonymous polymorphisms leading to amino acid change in MT-CYB (mitochondrially encoded cytochrome b) and in MT-ND1 (mitochondrially encoded NADH dehydrogenase 1) genes. We identified chrM_16189 variant (non-protein coding variant) in 40% (6/15) of nonrecurrent adenomas compared to recurrent ones where this variant was not present (0/11) (p=0.0209). Conclusions Next-generation sequencing is a reliable method for investigating mitochondrial genome and heteroplasmy in pituitary adenomas. In pituitary adenomas the prevalence of heteroplasmy of mitochondrial genome is low suggesting that these alterations may not influence mitochondrial function considerably. Of pituitary tumours only null cell adenomas possess alterations of mitochondrial genome with potential functional consequences suggesting that during the development of this subtype of pituitary tumours mitochondrial function-associated mechanisms may have role

Ser80Ile mutation and a concurrent Pro25Leu variant of the VHL gene in an extended Hungarian von Hippel-Lindau family

Von Hippel-Lindau disease (VHL) is a rare autosomal dominant disease characterized by development of cystic and tumorous lesions at multiple sites, including the brain, spinal cord, kidneys, adrenals, pancreas, epididymis and eyes. The clinical phenotype results from molecular abnormalities of the VHL tumor suppressor gene, mapped to human chromosome 3p25-26. The VHL gene encodes two functionally active VHL proteins due to the presence of two translational initiation sites separated by 53 codons. The majority of disease-causing mutations have been detected downstream of the second translational initiation site, but there are conflicting data as to whether few mutations located in the first 53 codons, such as the Pro25Leu could have a pathogenic role. In this paper we report a large Hungarian VHL type 2 family consisting of 32 members in whom a disease-causing AGT80AAT (Ser80Ile) c.239G>A, p.Ser80Ile mutation, but not the concurrent CCT25CTT (Pro25Leu) c.74C>T, p.Pro25Leu variant co-segregated with the disease. To our knowledge, the Ser80Ile mutation has not been previously described in VHL type 2 patients with high risk of pheochromocytoma and renal cell cancer. Therefore, this finding represents a novel genotype-phenotype association and VHL kindreds with Ser80Ile mutation will require careful surveillance for pheochromocytoma. We concluded that the Pro25Leu variant is a rare, neutral variant, but the presence such a rare gene variant may make genetic counseling difficult

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Juxtaposing BTE and ATE – on the role of the European insurance industry in funding civil litigation

One of the ways in which legal services are financed, and indeed shaped, is through private insurance arrangement. Two contrasting types of legal expenses insurance contracts (LEI) seem to dominate in Europe: before the event (BTE) and after the event (ATE) legal expenses insurance. Notwithstanding institutional differences between different legal systems, BTE and ATE insurance arrangements may be instrumental if government policy is geared towards strengthening a market-oriented system of financing access to justice for individuals and business. At the same time, emphasizing the role of a private industry as a keeper of the gates to justice raises issues of accountability and transparency, not readily reconcilable with demands of competition. Moreover, multiple actors (clients, lawyers, courts, insurers) are involved, causing behavioural dynamics which are not easily predicted or influenced. Against this background, this paper looks into BTE and ATE arrangements by analysing the particularities of BTE and ATE arrangements currently available in some European jurisdictions and by painting a picture of their respective markets and legal contexts. This allows for some reflection on the performance of BTE and ATE providers as both financiers and keepers. Two issues emerge from the analysis that are worthy of some further reflection. Firstly, there is the problematic long-term sustainability of some ATE products. Secondly, the challenges faced by policymakers that would like to nudge consumers into voluntarily taking out BTE LEI

Penilaian Kinerja Keuangan Koperasi di Kabupaten Pelalawan

This paper describe development and financial performance of cooperative in District Pelalawan among 2007 - 2008. Studies on primary and secondary cooperative in 12 sub-districts. Method in this stady use performance measuring of productivity, efficiency, growth, liquidity, and solvability of cooperative. Productivity of cooperative in Pelalawan was highly but efficiency still low. Profit and income were highly, even liquidity of cooperative very high, and solvability was good

Search for stop and higgsino production using diphoton Higgs boson decays

Results are presented of a search for a "natural" supersymmetry scenario with gauge mediated symmetry breaking. It is assumed that only the supersymmetric partners of the top-quark (stop) and the Higgs boson (higgsino) are accessible. Events are examined in which there are two photons forming a Higgs boson candidate, and at least two b-quark jets. In 19.7 inverse femtobarns of proton-proton collision data at sqrt(s) = 8 TeV, recorded in the CMS experiment, no evidence of a signal is found and lower limits at the 95% confidence level are set, excluding the stop mass below 360 to 410 GeV, depending on the higgsino mass

Impacts of the Tropical Pacific/Indian Oceans on the Seasonal Cycle of the West African Monsoon

The current consensus is that drought has developed in the Sahel during the second half of the twentieth century as a result of remote effects of oceanic anomalies amplified by local land–atmosphere interactions. This paper focuses on the impacts of oceanic anomalies upon West African climate and specifically aims to identify those from SST anomalies in the Pacific/Indian Oceans during spring and summer seasons, when they were significant. Idealized sensitivity experiments are performed with four atmospheric general circulation models (AGCMs). The prescribed SST patterns used in the AGCMs are based on the leading mode of covariability between SST anomalies over the Pacific/Indian Oceans and summer rainfall over West Africa. The results show that such oceanic anomalies in the Pacific/Indian Ocean lead to a northward shift of an anomalous dry belt from the Gulf of Guinea to the Sahel as the season advances. In the Sahel, the magnitude of rainfall anomalies is comparable to that obtained by other authors using SST anomalies confined to the proximity of the Atlantic Ocean. The mechanism connecting the Pacific/Indian SST anomalies with West African rainfall has a strong seasonal cycle. In spring (May and June), anomalous subsidence develops over both the Maritime Continent and the equatorial Atlantic in response to the enhanced equatorial heating. Precipitation increases over continental West Africa in association with stronger zonal convergence of moisture. In addition, precipitation decreases over the Gulf of Guinea. During the monsoon peak (July and August), the SST anomalies move westward over the equatorial Pacific and the two regions where subsidence occurred earlier in the seasons merge over West Africa. The monsoon weakens and rainfall decreases over the Sahel, especially in August.Peer reviewe