A closed-form approximation for pricing temperature-based weather derivatives

This paper develops analytical distributions of temperature indices on which temperature derivatives are written. If the deviations of daily temperatures from their expected values are modelled as an Ornstein-Uhlenbeck process with timevarying variance, then the distributions of the temperature index on which the derivative is written is the sum of truncated, correlated Gaussian deviates. The key result of this paper is to provide an analytical approximation to the distribution of this sum, thus allowing the accurate computation of payoffs without the need for any simulation. A data set comprising average daily temperature spanning over a hundred years for four Australian cities is used to demonstrate the efficacy of this approach for estimating the payoffs to temperature derivatives. It is demonstrated that expected payoffs computed directly from historical records are a particularly poor approach to the problem when there are trends in underlying average daily temperature. It is shown that the proposed analytical approach is superior to historical pricing.

A high-throughput panel for identifying clinically relevant mutation profiles in melanoma

Success with molecular-based targeted drugs in the treatment of cancer has ignited extensive research efforts within the field of personalized therapeutics. However, successful application of such therapies is dependent on the presence or absence of mutations within the patient's tumor that can confer clinical efficacy or drug resistance. Building on these findings, we developed a high-throughput mutation panel for the identification of frequently occurring and clinically relevant mutations in melanoma. An extensive literature search and interrogation of the Catalogue of Somatic Mutations in Cancer database identified more than 1,000 melanoma mutations. Applying a filtering strategy to focus on mutations amenable to the development of targeted drugs, we initially screened 120 known mutations in 271 samples using the Sequenom MassARRAY system. A total of 252 mutations were detected in 17 genes, the highest frequency occurred in BRAF (n = 154, 57%), NRAS (n = 55, 20%), CDK4 (n = 8, 3%), PTK2B (n = 7, 2.5%), and ERBB4 (n = 5, 2%). Based on this initial discovery screen, a total of 46 assays interrogating 39 mutations in 20 genes were designed to develop a melanoma-specific panel. These assays were distributed in multiplexes over 8 wells using strict assay design parameters optimized for sensitive mutation detection. The final melanoma-specific mutation panel is a cost effective, sensitive, high-throughput approach for identifying mutations of clinical relevance to molecular-based therapeutics for the treatment of melanoma. When used in a clinical research setting, the panel may rapidly and accurately identify potentially effective treatment strategies using novel or existing molecularly targeted drugs

Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma

We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS. Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas. This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1P29S) in the highly conserved switch I domain. Crystal structures, and biochemical and functional studies of RAC1P29S showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration. These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit.

Identification of TFG (TRK-fused gene) as a putative metastatic melanoma tumor suppressor gene

High density SNP arrays can be used to identify DNA copy number changes in tumors such as homozygous deletions of tumor suppressor genes and focal amplifications of oncogenes. Illumina Human CNV370 Bead chip arrays were used to assess the genome for unbalanced chromosomal events occurring in 39 cell lines derived from stage III metastatic melanomas. A number of genes previously recognized to have an important role in the development and progression of melanoma were identified including homozygous deletions of CDKN2A (13 of 39 samples), CDKN2B (10 of 39), PTEN (3 of 39), PTPRD (3 of 39), TP53 (1 of 39), and amplifications of CCND1 (2 of 39), MITF (2 of 39), MDM2 (1 of 39), and NRAS (1 of 39). In addition, a number of focal homozygous deletions potentially targeting novel melanoma tumor suppressor genes were identified. Because of their likely functional significance for melanoma progression, FAS, CH25H, BMPR1A, ACTA2, and TFG were investigated in a larger cohort of melanomas through sequencing. Nonsynonymous mutations were identified in BMPR1A (1 of 43), ACTA2 (3 of 43), and TFG (5 of 103). A number of potentially important mutation events occurred in TFG including the identification of a mini mutation ‘‘hotspot’’ at amino acid residue 380 (P380S and P380L) and the presence of multiple mutations in two melanomas. Mutations in TFG may have important clinical relevance for current therapeutic strategies to treat metastatic melanoma.

Whole genome and exome sequencing of melanoma

Melanoma has historically been refractive to traditional therapeutic approaches. As such, the development of novel drug strategies has been needed to improve rates of overall survival in patients with melanoma, particularly those with late stage or disseminated disease. Recent success with molecularly based targeted drugs, such as Vemurafenib in BRAF-mutant melanomas, has now made “personalized medicine” a reality within some oncology clinics. In this sense, tailored drugs can be administered to patients according to their tumor “mutation profiles.” The success of these drug strategies, in part, can be attributed to the identification of the genetic mechanisms responsible for the development and progression of metastatic melanoma. Recently, the advances in sequencing technology have allowed for comprehensive mutation analysis of tumors and have led to the identification of a number of genes involved in the etiology of metastatic melanoma. As the methodology and costs associated with next-generation sequencing continue to improve, this technology will be rapidly adopted into routine clinical oncology practices and will significantly impact on personalized therapy. This review summarizes current and emerging molecular targets in metastatic melanoma, discusses the potential application of next-generation sequencing within the paradigm of personalized medicine, and describes the current limitations for the adoption of this technology within the clinic.

Prognostic value of hTERT mRNA expression in surgical samples of lung cancer patients : the European Early Lung Cancer Project

Lung cancer is the most important cause of cancer-related mortality. Resectability and eligibility for treatment with adjuvant chemotherapy is determined by staging according to the TNM classification. Other determinants of tumour behaviour that predict disease outcome, such as molecular markers, may improve decision-making. Activation of the gene encoding human telomerase reverse transcriptase (hTERT) is implicated in the pathogenesis of lung cancer, and consequently detection of hTERT mRNA might have prognostic value for patients with early stage lung cancer. A cohort of patients who underwent a complete resection for early stage lung cancer was recruited as part of the European Early Lung Cancer (EUELC) project. In 166 patients expression of hTERT mRNA was determined in tumour tissue by quantitative real-time RT-PCR and related to that of a house-keeping gene (PBGD). Of a subgroup of 130 patients tumour-distant normal tissue was additionally available for hTERT mRNA analysis. The correlation between hTERT levels of surgical samples and disease-free survival was determined using a Fine and Gray hazard model. Although hTERT mRNA positivity in tumour tissue was significantly associated with clinical stage (Fisher's exact test p=0.016), neither hTERT mRNA detectability nor hTERT mRNA levels in tumour tissue were associated with clinical outcome. Conversely, hTERT positivity in adjacent normal samples was associated with progressive disease, 28% of patients with progressive disease versus 7.5% of disease-free patients had detectable hTERT mRNA in normal tissue [adjusted HR: 3.60 (1.64-7.94), p=0.0015]. hTERT mRNA level in tumour tissue has no prognostic value for patients with early stage lung cancer. However, detection of hTERT mRNA expression in tumour-distant normal lung tissue may indicate an increased risk of progressive disease.

The impact of heatwaves on mortality and emergency hospital admissions from non-external causes in Brisbane, Australia

Objectives Heatwaves can have significant health consequences resulting in increased mortality and morbidity. However, their impact on people living in tropical/subtropical regions remains largely unknown. This study assessed the impact of heatwaves on mortality and emergency hospital admissions (EHAs) from non-external causes (NEC) in Brisbane, a subtropical city in Australia. Methods We acquired daily data on weather, air pollution and EHAs for patients aged 15 years and over in Brisbane between January 1996 and December 2005, and on mortality between January 1996 and November 2004. A locally derived definition of heatwave (daily maximum ≥37°C for 2 or more consecutive days) was adopted. Case–crossover analyses were used to assess the impact of heatwaves on cause-specific mortality and EHAs. Results During heatwaves, there was a statistically significant increase in NEC mortality (OR 1.46; 95% CI 1.21 to 1.77), cardiovascular mortality (OR 1.89; 95% CI 1.44 to 2.48), diabetes mortality in those aged 75+ (OR 9.96; 95% CI 1.02 to 96.85), NEC EHAs (OR 1.15; 95% CI 1.07 to 1.23) and EHAs from renal diseases (OR 1.41; 95% CI 1.09 to 1.83). The elderly were found to be particularly vulnerable to heatwaves (eg, for NEC EHAs, OR 1.24 for 65–74-year-olds and 1.39 for those aged 75+). Conclusions Significant increases in NEC mortality and EHAs were observed during heatwaves in Brisbane where people are well accustomed to hot summer weather. The most vulnerable were the elderly and people with cardiovascular, renal or diabetic disease.

Analysis of terrain geometry representations for traversability of a Mars rover

For a planetary rover to successfully traverse across unstructured terrain autonomously, one of the major challenges is to assess its local traversability such that it can plan a trajectory to achieve its mission goals efficiently while minimising risk to the vehicle itself. This paper aims to provide a comparative study on different approaches for representing the geometry of Martian terrain for the purpose of evaluating terrain traversability. An accurate representation of the geometric properties of the terrain is essential as it can directly affect the determination of traversability for a ground vehicle. We explore current state-of-the-art techniques for terrain estimation, in particular Gaussian Processes (GP) in various forms, and discuss the suitability of each technique in the context of an unstructured Martian terrain. Furthermore, we present the limitations of regression techniques in terms of spatial correlation and continuity assumptions, and the impact on traversability analysis of a planetary rover across unstructured terrain. The analysis was performed on datasets of the Mars Yard at the Powerhouse Museum in Sydney, obtained using the onboard RGB-D camera.

A near-to-far non-parametric learning approach for estimating traversability in deformable terrain

It is well recognized that many scientifically interesting sites on Mars are located in rough terrains. Therefore, to enable safe autonomous operation of a planetary rover during exploration, the ability to accurately estimate terrain traversability is critical. In particular, this estimate needs to account for terrain deformation, which significantly affects the vehicle attitude and configuration. This paper presents an approach to estimate vehicle configuration, as a measure of traversability, in deformable terrain by learning the correlation between exteroceptive and proprioceptive information in experiments. We first perform traversability estimation with rigid terrain assumptions, then correlate the output with experienced vehicle configuration and terrain deformation using a multi-task Gaussian Process (GP) framework. Experimental validation of the proposed approach was performed on a prototype planetary rover and the vehicle attitude and configuration estimate was compared with state-of-the-art techniques. We demonstrate the ability of the approach to accurately estimate traversability with uncertainty in deformable terrain.

Traversability estimation for a planetary rover via experimental kernel learning in a Gaussian process framework

A critical requirement for safe autonomous navigation of a planetary rover is the ability to accurately estimate the traversability of the terrain. This work considers the problem of predicting the attitude and configuration angles of the platform from terrain representations that are often incomplete due to occlusions and sensor limitations. Using Gaussian Processes (GP) and exteroceptive data as training input, we can provide a continuous and complete representation of terrain traversability, with uncertainty in the output estimates. In this paper, we propose a novel method that focuses on exploiting the explicit correlation in vehicle attitude and configuration during operation by learning a kernel function from vehicle experience to perform GP regression. We provide an extensive experimental validation of the proposed method on a planetary rover. We show significant improvement in the accuracy of our estimation compared with results obtained using standard kernels (Squared Exponential and Neural Network), and compared to traversability estimation made over terrain models built using state-of-the-art GP techniques.

Estrogen receptor β activation impairs mitochondrial oxidative metabolism and affects malignant mesothelioma cell growth in vitro and in vivo

Estrogen receptor (ER)-β has been shown to possess a tumor suppressive effect, and is a potential target for cancer therapy. Using gene-expression meta-analysis of human malignant pleural mesothelioma, we identified an ESR2 (ERβ coding gene) signature. High ESR2 expression was strongly associated with low succinate dehydrogenase B (SDHB) (which encodes a mitochondrial respiratory chain complex II subunit) expression. We demonstrate that SDHB loss induced ESR2 expression, and that activated ERβ, by over-expression or by selective agonist stimulation, negatively affected oxidative phosphorylation compromising mitochondrial complex II and IV activity. This resulted in reduced mitochondrial ATP production, increased glycolysis dependence and impaired cell proliferation. The observed in vitro effects were phenocopied in vivo using a selective ERβ agonist in a mesothelioma mouse model. On the whole, our data highlight an unforeseen interaction between ERβ-mediated tumor suppression and energy metabolism that may be exploited to improve on the therapy for clinical management of malignant mesothelioma.

Global analysis of serum microRNAs as potential biomarkers for lung adenocarcinoma

Early diagnosis and the ability to predict the most relevant treatment option for individuals is essential to improve clinical outcomes for non-small cell lung cancer (NSCLC) patients. Adenocarcinoma (ADC), a subtype of NSCLC, is the single biggest cancer killer and therefore an urgent need to identify minimally invasive biomarkers to enable early diagnosis. Recent studies, by ourselves and others, indicate that circulating miRNA s have potential as biomarkers. Here we applied global profiling approaches in serum from patients with ADC of the lung to explore if miRNA s have potential as diagnostic biomarkers. This study involved RNA isolation from 80 sera specimens including those from ADC patients (equal numbers of stages 1, 2, 3, and 4) and age- and gender-matched controls (n = 40 each). Six hundred and sixty-seven miRNA s were co-analyzed in these specimens using TaqMan low density arrays and qPCR validation using individual miRNA s. Overall, approximately 390 and 370 miRNA s were detected in ADC and control sera, respectively. A group of 6 miRNA s, miR-30c-1* (AU C = 0.74; P < 0.002), miR-616(AU C = 0.71; P = 0.001), miR-146b-3p (AU C = 0.82; P < 0.0001), miR-566 (AU C = 0.80; P < 0.0001), miR-550 (AU C = 0.72; P = 0.0006), and miR-939 (AU C = 0.82; P < 0.0001) was found to be present at substantially higher levels in ADC compared with control sera. Conversely, miR-339-5p and miR-656 were detected at substantially lower levels in ADC sera (co-analysis resulting in AU C = 0.6; P = 0.02). Differences in miRNA profile identified support circulating miRNA s having potential as diagnostic biomarkers for ADC. More extensive studies of ADC and control serum specimens are warranted to independently validate the potential clinical relevance of these miRNA s as minimally invasive biomarkers for ADC.

Influence and increased funding in Canadian public libraries : the case of Alberta in fiscal year 2009–10

This exploratory case study examined the role of social influence in the decision-making process to increase public library funding in the Canadian province of Alberta in the 2009–10 fiscal year. Using Robert Cialdini’s theory of factors of influence (i.e., commitment and consistency, authority, liking, social proof, scarcity, and reciprocity) as a framework for analysis, findings show that consistency and commitment and authority were relevant and that liking was also important. These findings are consistent with Cialdini’s theory, which suggests that the quality of relationships is one factor that can most strongly influence a decision maker. This study gives insight into the factors motivating those involved in public library funding allocation decisions. No prior studies have examined the construct of influence in decision making about funding for public libraries at any level of government.

The role of interpersonal influence in budget decision making: The Canadian public library experience

This study determined factors which influenced Canadian provincial (state) politicians when making funding decisions for public libraries. Using the case study methodology, Canadian provincial/state-level funding for public libraries in the 2009-2010 fiscal year was examined. The data were analyzed to determine whether Cialdini’s theory of influence and specifically any of the six tactics of influence (i.e., commitment and consistency, authority, liking, social proof, scarcity, and reciprocity) were instrumental in these budgetary decision-making processes. Findings show the principles of “authority,” “consistency and commitment,” and “liking” were relevant, and that “liking” was especially important to these decisions.

A large proportion of asymptomatic Plasmodium infections with low and sub-microscopic parasite densities in the low transmission setting of Temotu Province, Solomon Islands : challenges for malaria diagnostics in an elimination setting

Background Many countries are scaling up malaria interventions towards elimination. This transition changes demands on malaria diagnostics from diagnosing ill patients to detecting parasites in all carriers including asymptomatic infections and infections with low parasite densities. Detection methods suitable to local malaria epidemiology must be selected prior to transitioning a malaria control programme to elimination. A baseline malaria survey conducted in Temotu Province, Solomon Islands in late 2008, as the first step in a provincial malaria elimination programme, provided malaria epidemiology data and an opportunity to assess how well different diagnostic methods performed in this setting. Methods During the survey, 9,491 blood samples were collected and examined by microscopy for Plasmodium species and density, with a subset also examined by polymerase chain reaction (PCR) and rapid diagnostic tests (RDTs). The performances of these diagnostic methods were compared. Results A total of 256 samples were positive by microscopy, giving a point prevalence of 2.7%. The species distribution was 17.5% Plasmodium falciparum and 82.4% Plasmodium vivax. In this low transmission setting, only 17.8% of the P. falciparum and 2.9% of P. vivax infected subjects were febrile (≥38°C) at the time of the survey. A significant proportion of infections detected by microscopy, 40% and 65.6% for P. falciparum and P. vivax respectively, had parasite density below 100/μL. There was an age correlation for the proportion of parasite density below 100/μL for P. vivax infections, but not for P. falciparum infections. PCR detected substantially more infections than microscopy (point prevalence of 8.71%), indicating a large number of subjects had sub-microscopic parasitemia. The concordance between PCR and microscopy in detecting single species was greater for P. vivax (135/162) compared to P. falciparum (36/118). The malaria RDT detected the 12 microscopy and PCR positive P. falciparum, but failed to detect 12/13 microscopy and PCR positive P. vivax infections. Conclusion Asymptomatic malaria infections and infections with low and sub-microscopic parasite densities are highly prevalent in Temotu province where malaria transmission is low. This presents a challenge for elimination since the large proportion of the parasite reservoir will not be detected by standard active and passive case detection. Therefore effective mass screening and treatment campaigns will most likely need more sensitive assays such as a field deployable molecular based assay.