An empirical comparison using both the term structure of interest rates and alternative models in pricing options on 90-day BAB futures

The use of the term structure of interest rates to price options is relatively new in the literature. It describes the relationship between interest rates and the maturities of bonds. The first model that described the interest rate process was the Vasicek (1977) model. There have been many studies on the formulation of theoretical pricing models. Yet limited empirical research has been done in the area of actually testing the models. In this thesis we report the results of a set of tests of the models indicated below. This paper involves analysis of the pricing errors of the Black model ( 1976), Asay model (1982), Extended-Vasicek model (1990) and Heath-Jarrow-Morton model (HJM) ( 1992) as applied to call options on 90-day Bank Accepted Bill (BAB) futures. Monthly yield curves are generated from cash, futures, swap and interest rate cap data. A number of different methods of analysis are used. These include the use of inferential statistics, non-parametric sign tests and Ordinary Least Square Regressions. The Wilcoxon non-parametric sign test assists the interpretation of whether the pricing errors are from the same distribution. Ordinary Least Square Regressions are used to assess the significance of factors affecting pricing errors. In addition, data are plotted against different variables in order to show any systematic patterns in how pricing errors are affected by the changes in the chosen variables. Monthly options data on BAB futures in the year 1996 suggest that the term structure models have significantly lower pricing errors than the Black and the Asay model. The Heath-Jarrow-Morton model (1992) is overall the better model to use. For the term structure models, pricing errors show a decreasing trend as moneyness increases. The Extended-Vasicek model and the HJM model have significantly lower errors for deep-in the-money and out-of-the-money options. Higher mean absolute errors are observed for at-the-money options for both term structure models. The HJM model overprices at-the money options but underprices in and out-of-the-money options while the Extended Vasicek model underprices deep-in-the-money options but overprices options of other categories. The mean and absolute errors for both the Black model and the Asay model rise as time to maturity and volatility increases. The two models overprice in, at and out-of-the money options and the mean pricing error is lowest for in-the-money options. The results suggest that the factor time to maturity is significant at the 0.05 level to the -mean pricing error for all four models. Moneyness is the only insignificant factor when the Asay model is used. It is also negatively correlated to mean pricing error for the Black model, the Asay model, the Extended-Vasicek model and the HJM model. The R-square for the Extended-Vasicek model was found to be the lowest. Overall, the HJM model gives the lowest pricing error when pricing options on 90-Day Bank Accepted Bill Futures

The neural bases for devaluing radical political statements revealed by penetrating traumatic brain injury

Given the determinant role of ventromedial prefrontal cortex (vmPFC) in valuation, we examined whether vmPFC lesions also modulate how people scale political beliefs. Patients with penetrating traumatic brain injury (pTBI; N1/4102) and healthy controls (HCs; N1/431) were tested on the political belief task, where they rated 75 statements expressing political opinions concerned with welfare, economy, political involvement, civil rights, war and security. Each statement was rated for level of agreement and scaled along three dimensions: radicalism, individualism and conservatism. Voxel-based lesionsymptom mapping (VLSM) analysis showed that diminished scores for the radicalism dimension (i.e. statements were rated as less radical than the norms) were associated with lesions in bilateral vmPFC. After dividing the pTBI patients into three groups, according to lesion location (i.e. vmPFC, dorsolateral prefrontal cortex [dlPFC] and parietal cortex), we found that the vmPFC, but not the dlPFC, group had reduced radicalism scores compared with parietal and HC groups. These findings highlight the crucial role of the vmPFC in appropriately valuing political behaviors and may explain certain inappropriate social judgments observed in patients with vmPFC lesions

Transformación de los liderazgos en la minería: gestión estratégica para incorporar mujeres a la industria

La menor participación de las mujeres en la industria minera predomina a nivel internacional. En Chile, a pesar de las mayores remuneraciones, del nivel tecnológico y del déficit proyectado de capital humano en el sector, las mujeres representan el 4,2% en las áreas operacionales. El objetivo de este trabajo es analizar el rol de las jefaturas mineras para revertir esta condición. Con un estudio de caso, en la Compañía Minera Esperanza perteneciente al grupo Antofagasta Minerals, ubicada en el norte de Chile, se entrevistaron en profundidad a nueve jefes de áreas operacionales.Los resultados reportan lo imperativo de ejercer un liderazgo transformacional con perspectiva de género y con ello flexibilizar la gestión del recurso humano, facilitar la adaptación y proyección de las mujeres, promover las jefaturas femeninas y adjudicar a los jefes la responsabilidad de una gestión más simétrica. Estos hallazgos son centrales para una gestión estratégica en una industria que experimenta una alta demanda y un intenso dinamismo a nivel internacional

Gefitinib and <i>EGFR</i> Gene Copy Number Aberrations in Esophageal Cancer

Purpose: The cancer esophagus gefitinib (COG) trial demonstrated improved progression free survival with the Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI), gefitinib relative to placebo in advanced esophageal cancer patients with disease progression after chemotherapy. Rapid and durable responses were observed in a minority. We hypothesised that genetic aberration of the EGFR pathway would identify patients benefitting from gefitinib. Patients and Methods: A pre-specified blinded molecular analysis of COG trial tumours was conducted to compare efficacy of gefitinib to placebo according to EGFR copy number gain (CNG) and EGFR, KRAS, BRAF and PIK3CA mutation status. EGFR CNG was determined by fluorescent insitu hybridisation (FISH) using pre-specified criteria and EGFR FISH positive defined as high polysomy or amplification. Results: Biomarker data were available for 340 patients. In EGFR FISH positive tumours (20.2%) overall survival was improved with gefitinib compared to placebo (hazard ratio [HR] for death, 0.59; 95% confidence interval [CI], 0.35, 1.00 p=0.05). In EGFR FISH negative tumours there was no difference in overall survival with gefitinib compared to placebo (HR for death, 0.90, 95% CI 0.69, 1.18 p=0.46). EGFR amplification (7.2%) patients gained greatest benefit from gefitinib (HR for death, 0.21; 95% CI 0.07-0.64; p=0.006). There was no difference in overall survival for gefitinib versus placebo for patients with EGFR, KRAS, BRAF and PIK3CA mutations, or for any mutation versus none. Conclusion: EGFR CNG assessed by FISH appears to identify a subgroup of esophageal cancer patients who may benefit from gefitinib as a second line treatment, and suggests that anti-EGFR 3 therapies should be investigated in prospective clinical trials in different settings in EGFR FI SH positive, and in particular EGFR amplified, esophageal cancer

An Allosteric Inhibitor of Protein Arginine Methyltransferase 3

PRMT3, a protein arginine methyltransferase, has been shown to influence ribosomal biosynthesis by catalyzing the dimethylation of the 40S ribosomal protein S2. Although PRMT3 has been reported to be a cytosolic protein, it has been shown to methylate histone H4 peptide (H4 1-24) in vitro. Here, we report the identification of a PRMT3 inhibitor (1-(benzo[d][1,2,3]thiadiazol-6-yl)-3-(2-cyclohexenylethyl)urea; compound 1) with IC50 value of 2.5 μM by screening a library of 16,000 compounds using H4 (1-24) peptide as a substrate. The crystal structure of PRMT3 in complex with compound 1 as well as kinetic analysis reveals an allosteric mechanism of inhibition. Mutating PRMT3 residues within the allosteric site or using compound 1 analogs that disrupt interactions with allosteric site residues both abrogated binding and inhibitory activity. These data demonstrate an allosteric mechanism for inhibition of protein arginine methyltransferases, an emerging class of therapeutic targets

Development of a Clinical Prediction Score Including Monocyte-to-Lymphocyte Ratio to Inform Tuberculosis Treatment Among Children With HIV: A Multicountry Study

BACKGROUND: Clinical pediatric tuberculosis (TB) diagnosis may lead to overdiagnosis particularly among children with human immunodeficiency virus (CHIV). We assessed the performance of monocyte-lymphocyte ratio (MLR) as a diagnostic biomarker and constructed a clinical prediction score to improve specificity of TB diagnosis in CHIV with limited access to microbiologic testing. METHODS: We pooled data from cohorts of children aged ≤13 years from Vietnam, Cameroon, and South Africa to validate the use of MLR ≥0.378, previously found as a TB diagnostic marker among CHIV. Using multivariable logistic regression, we created an internally validated prediction score for diagnosis of TB disease in CHIV. RESULTS: The combined cohort had 601 children (median age, 1.9 [interquartile range, 0.9-5.3] years); 300 (50%) children were male, and 283 (47%) had HIV. Elevated MLR ≥0.378 had sensitivity of 36% (95% confidence interval [CI], 23%-51%) and specificity of 79% (95% CI, 71%-86%) among CHIV in the validation cohort. A model using MLR ≥0.28, age ≥4 years, tuberculin skin testing ≥5 mm, TB contact history, fever >2 weeks, and chest radiograph suggestive of TB predicted active TB disease in CHIV with an area under the receiver operating characteristic curve of 0.85. A prediction score of ≥5 points had a sensitivity of 94% and specificity of 48% to identify confirmed TB, and a sensitivity of 82% and specificity of 48% to identify confirmed and unconfirmed TB groups combined. CONCLUSIONS: Our score has comparable sensitivity and specificity to algorithms including microbiological testing and should enable clinicians to rapidly initiate TB treatment among CHIV when microbiological testing is unavailable

Mapping genetic vulnerabilities reveals BTK as a novel therapeutic target in oesophageal cancer

Objective Oesophageal cancer is the seventh most common cause of cancer-related death worldwide. Disease relapse is frequent and treatment options are limited. Design To identify new biomarker-defined therapeutic approaches for patients with oesophageal cancer, we integrated the genomic profiles of 17 oesophageal tumour-derived cell lines with drug sensitivity data from small molecule inhibitor profiling, identifying drug sensitivity effects associated with cancer driver gene alterations. We also interrogated recently described RNA interference screen data for these tumour cell lines to identify candidate genetic dependencies or vulnerabilities that could be exploited as therapeutic targets. Results By integrating the genomic features of oesophageal tumour cell lines with siRNA and drug screening data, we identified a series of candidate targets in oesophageal cancer, including a sensitivity to inhibition of the kinase BTK in MYC amplified oesophageal tumour cell lines. We found that this genetic dependency could be elicited with the clinical BTK/ERBB2 kinase inhibitor, ibrutinib. In both MYC and ERBB2 amplified tumour cells, ibrutinib downregulated ERK-mediated signal transduction, cMYC Ser-62 phosphorylation and levels of MYC protein, and elicited G(1) cell cycle arrest and apoptosis, suggesting that this drug could be used to treat biomarker-selected groups of patients with oesophageal cancer. Conclusions BTK represents a novel candidate therapeutic target in oesophageal cancer that can be targeted with ibrutinib. On the basis of this work, a proof-of-concept phase II clinical trial evaluating the efficacy of ibrutinib in patients with MYC and/or ERBB2 amplified advanced oesophageal cancer is currently underway (NCT02884453). Trial registration number NCT02884453; Pre-result

Discovery of a 2,4-Diamino-7-aminoalkoxyquinazoline as a Potent and Selective Inhibitor of Histone Lysine Methyltransferase G9a

SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template led to the discovery of 8 (UNC0224) as a potent and selective G9a inhibitor. A high resolution X-ray crystal structure of the G9a-8 complex, the first co-crystal structure of G9a with a small molecule inhibitor, was obtained. The co-crystal structure validated our binding hypothesis and will enable structure-based design of novel inhibitors. 8 is a useful tool for investigating the biology of G9a and its roles in chromatin remodeling

Protein Lysine Methyltransferase G9a Inhibitors: Design, Synthesis, and Structure Activity Relationships of 2,4-Diamino-7-aminoalkoxy-quinazolines.

Protein lysine methyltransferase G9a, which catalyzes methylation of lysine 9 of histone H3 (H3K9) and lysine 373 (K373) of p53, is over expressed in human cancers. Genetic knockdown of G9a inhibits cancer cell growth and the di-methylation of p53 K373 results in the inactivation of p53. Initial SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template represented by 3a (BIX01294), a selective small molecule inhibitor of G9a and GLP, led to the discovery of 10 (UNC0224) as a potent G9a inhibitor with excellent selectivity. A high resolution X-ray crystal structure of the G9a-10 complex, the first co-crystal structure of G9a with a small molecule inhibitor, was obtained. Based on the structural insights revealed by this co-crystal structure, optimization of the 7-dimethylaminopropoxy side chain of 10 resulted in the discovery of 29 (UNC0321) (Morrison Ki = 63 pM), which is the first G9a inhibitor with picomolar potency and the most potent G9a inhibitor to date