Functional Variants in Notch Pathway Genes NCOR2, NCSTN, and MAML2 Predict Survival of Patients with Cutaneous Melanoma.

BACKGROUND: The Notch signaling pathway is constitutively activated in human cutaneous melanoma to promote growth and aggressive metastatic potential of primary melanoma cells. Therefore, genetic variants in Notch pathway genes may affect the prognosis of cutaneous melanoma patients. METHODS: We identified 6,256 SNPs in 48 Notch genes in 858 cutaneous melanoma patients included in a previously published cutaneous melanoma genome-wide association study dataset. Multivariate and stepwise Cox proportional hazards regression and false-positive report probability corrections were performed to evaluate associations between putative functional SNPs and cutaneous melanoma disease-specific survival. Receiver operating characteristic curve was constructed, and area under the curve was used to assess the classification performance of the model. RESULTS: Four putative functional SNPs of Notch pathway genes had independent and joint predictive roles in survival of cutaneous melanoma patients. The most significant variant was NCOR2 rs2342924 T>C (adjusted HR, 2.71; 95% confidence interval, 1.73-4.23; Ptrend = 9.62 × 10(-7)), followed by NCSTN rs1124379 G>A, NCOR2 rs10846684 G>A, and MAML2 rs7953425 G>A (Ptrend = 0.005, 0.005, and 0.013, respectively). The receiver operating characteristic analysis revealed that area under the curve was significantly increased after adding the combined unfavorable genotype score to the model containing the known clinicopathologic factors. CONCLUSIONS: Our results suggest that SNPs in Notch pathway genes may be predictors of cutaneous melanoma disease-specific survival. IMPACT: Our discovery offers a translational potential for using genetic variants in Notch pathway genes as a genotype score of biomarkers for developing an improved prognostic assessment and personalized management of cutaneous melanoma patients.

Polymorphisms in the kinesin-like factor 1 B gene and risk of epithelial ovarian cancer in Eastern Chinese women.

The kinesin-like factor 1 B (KIF1B) gene plays an important role in the process of apoptosis and the transformation and progression of malignant cells. Genetic variations in KIF1B may contribute to risk of epithelial ovarian cancer (EOC). In this study of 1,324 EOC patients and 1,386 cancer-free female controls, we investigated associations between two potentially functional single nucleotide polymorphisms in KIF1B and EOC risk by the conditional logistic regression analysis. General linear regression model was used to evaluate the correlation between the number of variant alleles and KIF1B mRNA expression levels. We found that the rs17401966 variant AG/GG genotypes were significantly associated with a decreased risk of EOC (adjusted odds ratio (OR) = 0.81, 95 % confidence interval (CI) = 0.68-0.97), compared with the AA genotype, but no associations were observed for rs1002076. Women who carried both rs17401966 AG/GG and rs1002076 AG/AA genotypes of KIF1B had a 0.82-fold decreased risk (adjusted 95 % CI = 0.69-0.97), compared with others. Additionally, there was no evidence of possible interactions between about-mentioned co-variants. Further genotype-phenotype correlation analysis indicated that the number of rs17401966 variant G allele was significantly associated with KIF1B mRNA expression levels (P for GLM = 0.003 and 0.001 in all and Chinese subjects, respectively), with GG carriers having the lowest level of KIF1B mRNA expression. Taken together, the rs17401966 polymorphism likely regulates KIF1B mRNA expression and thus may be associated with EOC risk in Eastern Chinese women. Larger, independent studies are warranted to validate our findings.

Quantitative genetics of CTCF binding reveal local sequence effects and different modes of X-chromosome association.

Associating genetic variation with quantitative measures of gene regulation offers a way to bridge the gap between genotype and complex phenotypes. In order to identify quantitative trait loci (QTLs) that influence the binding of a transcription factor in humans, we measured binding of the multifunctional transcription and chromatin factor CTCF in 51 HapMap cell lines. We identified thousands of QTLs in which genotype differences were associated with differences in CTCF binding strength, hundreds of them confirmed by directly observable allele-specific binding bias. The majority of QTLs were either within 1 kb of the CTCF binding motif, or in linkage disequilibrium with a variant within 1 kb of the motif. On the X chromosome we observed three classes of binding sites: a minority class bound only to the active copy of the X chromosome, the majority class bound to both the active and inactive X, and a small set of female-specific CTCF sites associated with two non-coding RNA genes. In sum, our data reveal extensive genetic effects on CTCF binding, both direct and indirect, and identify a diversity of patterns of CTCF binding on the X chromosome.

Variability in phenotype induced by the podocin variant R229Q plus a single pathogenic mutation.

BACKGROUND: Mutations in podocin (NPHS2) are the most common cause of childhood onset autosomal recessive steroid-resistant nephrotic syndrome (SRNS). The disease is characterized by early-onset proteinuria, resistance to immunosuppressive therapy and rapid progression to end-stage renal disease. Compound heterozygous changes involving the podocin variant R229Q combined with another pathogenic mutation have been associated with a mild phenotype with disease onset often in adulthood. METHODS: We screened 19 families with early-onset SRNS for mutations in NPHS2 and WT1 and identified four disease-causing mutations (three in NPHS2 and one in WT1) prior to planned whole-exome sequencing. RESULTS: We describe two families with three individuals presenting in childhood who are compound heterozygous for R229Q and one other pathogenic NPHS2 mutation, either L327F or A297V. One child presented at age 4 years (A297V plus R229Q) and the other two at age 13 (L327F plus R229Q), one with steadily deteriorating renal function. CONCLUSIONS: These cases highlight the phenotypic variability associated with the NPHS2 R229Q variant plus pathogenic mutation. Individuals may present with early aggressive disease.

Cannibal Animal Games: A new variant of Tic-Tac-Toe

This paper presents a new partial two-player game, called the cannibal animal game, which is a variant of Tic-Tac-Toe. The game is played on the infinite grid, where in each round a player chooses and occupies free cells. The first player Alice can occupy a cell in each turn and wins if she occupies a set of cells, the union of a subset of which is a translated, reflected and/or rotated copy of a previously agreed upon polyomino P (called an animal). The objective of the second player Bob is to prevent Alice from creating her animal by occupying in each round a translated, reflected and/or rotated copy of P. An animal is a cannibal if Bob has a winning strategy, and a non-cannibal otherwise. This paper presents some new tools, such as the bounding strategy and the punching lemma, to classify animals into cannibals or non-cannibals. We also show that the pairing strategy works for this problem.

Measurement of the cross section and angular correlations for associated production of a Z boson with b hadrons in pp collisions at √s = 7 TeV

A study of proton-proton collisions in which two b hadrons are produced in association with a Z boson is reported. The collisions were recorded at a centre-of-mass energy of 7TeV with the CMS detector at the LHC, for an integrated luminosity of 5:2 fb-1. The b hadrons are identified by means of displaced secondary vertices, without the use of reconstructed jets, permitting the study of b-hadron pair production at small angular separation. Differential cross sections are presented as a function of the angular separation of the b hadrons and the Z boson. In addition, inclusive measurements are presented. For both the inclusive and differential studies, different ranges of Z boson momentum are considered, and each measurement is compared to the predictions from different event generators at leading-order and next-to-leading-order accuracy. Copyright CERN.

Measuring the comprehensibility of Z specifications

The effects of natural language comments, meaningful variable names, and structure on the comprehensibility of Z specifications are investigated through a designed experiment conducted with a range of undergraduate and post-graduate student subjects. The times taken on three assessment questions are analysed and related to the abilities of the students as indicated by their total score, with the result that stronger students need less time than weaker students to complete the assessment. Individual question scores, and total score, are then analysed and the influence of comments, naming, structure and level of student's class are determined. In the whole experimental group, only meaningful naming significantly enhances comprehension. In contrast, for those obtaining the best score of 3/3 the only significant factor is commenting. Finally, the subjects' ratings of the five specifications used in the study in terms of their perceived comprehensibility have been analysed. Comments, naming and structure are again found to be of importance in the group when analysed as a whole, but in the sub-group of best performing subjects only the comments had an effect on perceived comprehensibility.

Evaluating the effectiveness of Z: The claims made about CICS and where we go from here

There have been few genuine success stories about industrial use of formal methods. Perhaps the best known and most celebrated is the use of Z by IBM (in collaboration with Oxford University's Programming Research Group) during the development of CICS/ESA (version 3.1). This work was rewarded with the prestigious Queen's Award for Technological Achievement in 1992 and is especially notable for two reasons: 1) because it is a commercial, rather than safety- or security-critical, system and 2) because the claims made about the effectiveness of Z are quantitative as well as qualitative. The most widely publicized claims are: less than half the normal number of customer-reported errors and a 9% savings in the total development costs of the release. This paper provides an independent assessment of the effectiveness of using Z on CICS based on the set of public domain documents. Using this evidence, we believe that the case study was important and valuable, but that the quantitative claims have not been substantiated. The intellectual arguments and rationale for formal methods are attractive, but their widespread commercial use is ultimately dependent upon more convincing quantitative demonstrations of effectiveness. Despite the pioneering efforts of IBM and PRG, there is still a need for rigorous, measurement-based case studies to assess when and how the methods are most effective. We describe how future similar case studies could be improved so that the results are more rigorous and conclusive.

[Book reviews] Review of J. E. Hoch, Semitic Words in Egyptian Texts of the New Kingdom and Third Intermediate Period and D. Sivan and Z. Cochavi-Rainey, West Semitic Vocabulary in Egyptian Script of the 14th to the 10th Centuries BCE

Reviews of: [1] James E. Hoch, Semitic Words in Egyptian Texts of the New Kingdom and Third Intermediate Period, (1994), Princeton University Press. [2] Daniel Sivan and Zipora Cochavi-Rainey, West Semitic Vocabulary in Egyptian Script of the 14th to the 10th Centuries BCE, (1992), Ben-Gurion University of the Negev Press.

Sensory neuropeptides induce histamine release from bronchoalveolar lavage cells in both nonasthmatic coughers and cough variant asthmatics

BACKGROUND: Sensory neuropeptides have been suggested to play a role in the pathogenesis of a number of respiratory diseases including asthma and chronic non-productive cough.

OBJECTIVES: To investigate the action of sensory neuropeptides on airway mast cells obtained by bronchoalveolar lavage (BAL).

METHODS: BAL was performed on 23 nonasthmatic patients with cough (NAC), 11 patients with cough variant asthma (CVA) and 10 nonatopic controls. Washed lavage cells were stimulated (20 min, 37 degrees C) with calcitonin gene-related peptide (CGRP), neurokinin A (NKA) and substance P (25 and 50 micromol/L).

RESULTS: The neuropeptides tested induced histamine release in all groups studied. Only CGRP (50 micromol/L) induced significantly more histamine release from both NAC and CVA patients compared with control subjects (P = 0.038 and 0.045, respectively).

CONCLUSION: Regardless of aetiology, mast cells from patients with chronic cough appear to have an increased responsiveness to CGRP compared with controls. The results of the present study suggest that the role of CGRP in chronic cough should be further investigated.