Overexpression of the mammalian target of rapamycin (mTOR) and angioinvasion are poor prognostic factors in early stage NSCLC: A verification study

Background: A recent study by Dhillon et al. [12], identified both angioinvasion and mTOR as prognostic biomarkers for poor survival in early stage NSCLC. The aim of this study was to verify the above study by examining the angioinvasion and mTOR expression profile in a cohort of early stage NSCLC patients and correlate the results to patient clinico-pathological data and survival. Methods: Angioinvasion was routinely recorded by the pathologist at the initial assessment of the tumor following resection. mTOR was evaluated in 141 early stage (IA-IIB) NSCLC patients (67 - squamous; 60 - adenocarcinoma; 14 - others) using immunohistochemistry (IHC) analysis with an immunohistochemical score (IHS) calculated (% positive cells × staining intensity). Intensity was scored as follows: 0 (negative); 1+ (weak); 2+ (moderate); 3+ (strong). The range of scores was 0-300. Based on the previous study a cut-off score of 30 was used to define positive versus negative patients. The impact of angioinvasion and mTOR expression on prognosis was then evaluated. Results: 101 of the 141 tumors studied expressed mTOR. There was no difference in mTOR expression between squamous cell carcinoma and adenocarcinoma. Angioinvasion (p= 0.024) and mTOR staining (p= 0.048) were significant univariate predictors of poor survival. Both remained significant after multivariate analysis (p= 0.037 and p= 0.020, respectively). Conclusions: Our findings verify angioinvasion and mTOR expression as new biomarkers for poor outcome in patients with early stage NSCLC. mTOR expressing patients may benefit from novel therapies targeting the mTOR survival pathway. © 2011 Elsevier Ireland Ltd.

Design, construction, and analysis of cell line arrays and tissue microarrays for gene expression analysis

Cell line array (CMA) and tissue microarray (TMA) technologies are high-throughput methods for analysing both the abundance and distribution of gene expression in a panel of cell lines or multiple tissue specimens in an efficient and cost-effective manner. The process is based on Kononen's method of extracting a cylindrical core of paraffin-embedded donor tissue and inserting it into a recipient paraffin block. Donor tissue from surgically resected paraffin-embedded tissue blocks, frozen needle biopsies or cell line pellets can all be arrayed in the recipient block. The representative area of interest is identified and circled on a haematoxylin and eosin (H&E)-stained section of the donor block. Using a predesigned map showing a precise spacing pattern, a high density array of up to 1,000 cores of cell pellets and/or donor tissue can be embedded into the recipient block using a tissue arrayer from Beecher Instruments. Depending on the depth of the cell line/tissue removed from the donor block 100-300 consecutive sections can be cut from each CMA/TMA block. Sections can be stained for in situ detection of protein, DNA or RNA targets using immunohistochemistry (IHC), fluorescent in situ hybridisation (FISH) or mRNA in situ hybridisation (RNA-ISH), respectively. This chapter provides detailed methods for CMA/TMA design, construction and analysis with in-depth notes on all technical aspects including tips to deal with common pitfalls the user may encounter. © Springer Science+Business Media, LLC 2011.

Phase II study of liarozole in advanced non-small cell lung cancer

The aim of this phase II study was to investigate the efficacy and tolerability of liarozole, a novel benzimidazole derivative, in non-small cell lung cancer (NSCLC). Liarozole 300 mg twice daily orally was evaluated in 14 patients with stage IIIB and IV NSCLC. 8 patients had received prior treatment with chemotherapy and/or radiotheraphy. WHO toxocity grading and response criteria were used. Liarozole was well tolerated. Grade 2 toxicities included alopecia (1 patient), dermatological toxicity (5 patients), dry mouth (2 patients) and nausea and vomiting (2 patients). Leukocytosis was seen in 5 patients, including 2 cases with an elevated white cell count pretreatment. Liarozole was discontinued in 1 patient who developed intolerable progressive pruritis associated with an erythematous rash. No objective tumour response was seen, all 14 patients developing progressive disease with 4 months of commencing treatment. Liarozole was well tolerated but was ineffective as single as single agent therapy in the management of NSCLC. The side-effect profile was compatible with inhibition of retinoic acid degradation.

A phase I dose-escalating study of DaunoXome, liposomal daunorubicin, in metastatic breast cancer

The aims of this phase I study were to establish the maximum tolerated dose, safety profile and activity of liposomal daunorubicin, DaunoXome (NeXstar Pharmaceuticals), in the treatment of metastatic breast cancer. DaunoXome was administered intravenously over 2 h in 21 day cycles and doses were increased from 80 to 100, 120 and 150 mg m 2. Sixteen patients were enrolled. A total of 70 cycles of DaunoXome were administered. The maximum tolerated dose was 120 mg m 2, the dose-limiting toxicity being prolonged grade 4 neutropenia or neutropenic pyrexia necessitating dose reductions at 120 and 150 mg m 2. Asymptomatic cardiotoxicity was observed in three patients: grade 1 in one treated with a cumulative dose of 800 mg m 2 and grade 2 in two, one who received a cumulative dose of 960 mg m 2 and the other a cumulative dose of 600 mg m 2 with a previous neoadjuvant doxorubicin chemotherapy of 300 mg m 2. Tumour response was evaluable in 15 patients, of whom two had objective responses, six had stable disease and seven had progressive disease. In conclusion, DaunoXome is associated with mild, manageable toxicities and has anti-tumour activity in metastatic breast cancer. The findings support further phase II evaluation of DaunoXome alone and in combination with other standard non-anthracycline cytotoxic or novel targeted agents. Although the dose-limiting toxicity for DaunoXome was febrile neutropenia at 120 mg m 2, we would recommend this dose for further evaluation, as the febrile neutropenia occurred after four or more cycles in three of the four episodes seen, was short lived and uncomplicated. © 2002 Cancer Research UK.

EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer : analysis of data from the phase 3 FLEX study

Background: Findings from the phase 3 First-Line ErbituX in lung cancer (FLEX) study showed that the addition of cetuximab to first-line chemotherapy significantly improved overall survival compared with chemotherapy alone (hazard ratio [HR] 0·871, 95% CI 0·762-0·996; p=0·044) in patients with advanced non-small-cell lung cancer (NSCLC). To define patients benefiting most from cetuximab, we studied the association of tumour EGFR expression level with clinical outcome in FLEX study patients. Methods: We used prospectively collected tumour EGFR expression data to generate an immunohistochemistry score for FLEX study patients on a continuous scale of 0-300. We used response data to select an outcome-based discriminatory threshold immunohistochemistry score for EGFR expression of 200. Treatment outcome was analysed in patients with low (immunohistochemistry score <200) and high (≥200) tumour EGFR expression. The primary endpoint in the FLEX study was overall survival. We analysed patients from the FLEX intention-to-treat (ITT) population. The FLEX study is registered with ClinicalTrials.gov, number NCT00148798. Findings: Tumour EGFR immunohistochemistry data were available for 1121 of 1125 (99·6%) patients from the FLEX study ITT population. High EGFR expression was scored for 345 (31%) evaluable patients and low for 776 (69%) patients. For patients in the high EGFR expression group, overall survival was longer in the chemotherapy plus cetuximab group than in the chemotherapy alone group (median 12·0 months [95% CI 10·2-15·2] vs 9·6 months [7·6-10·6]; HR 0·73, 0·58-0·93; p=0·011), with no meaningful increase in side-effects. We recorded no corresponding survival benefit for patients in the low EGFR expression group (median 9·8 months [8·9-12·2] vs 10·3 months [9·2-11·5]; HR 0·99, 0·84-1·16; p=0·88). A treatment interaction test assessing the difference in the HRs for overall survival between the EGFR expression groups suggested a predictive value for EGFR expression (p=0·044). Interpretation: High EGFR expression is a tumour biomarker that can predict survival benefit from the addition of cetuximab to first-line chemotherapy in patients with advanced NSCLC. Assessment of EGFR expression could offer a personalised treatment approach in this setting. Funding: Merck KGaA. © 2012 Elsevier Ltd.

Developing sustainable ‘liveable’ buildings, cities and communities for a sub-tropical context : residents’ perspectives

A key challenge for the 21st Century is to make our cities more liveable and foster economically sustainable, environmentally responsible, and socially inclusive communities. Design thinking, particularly a human-centred approach, offers a way to tackle this challenge. Findings from two recent Australian research projects highlight how facilitating sustainable, liveable communities in a humid sub-tropical environment requires an in-depth understanding of people’s perspectives, experiences and practices. Project 1 (‘Research House’) documents the reflections of a family who lived in a ‘test’ sustainable house for two years, outlining their experience and evaluations of universal design and sustainable technologies. The study family was very impressed with the natural lighting, natural ventilation, spaciousness and ease of access, which contributed significantly to their comfort and the liveability of their home. Project 2 (‘Inner-Urban High Density Living’) explored Brisbane residents’ opinions about high-density living, through a survey (n=636), interviews (n=24), site observations (over 300 hours) and environmental monitoring, assessing opinions on the liveability of their individual dwelling, the multi-unit host building and the surrounding neighbourhood. Nine areas, categorised into three general domains, were identified as essential for enhancing high density liveability. In terms of the dwelling, thermal comfort/ventilation, natural light, noise mitigation were important; shared space, good neighbour protocols, and support for environmentally sustainable behaviour were desired in the building/complex; and accessible/sustainable transport, amenities and services, sense of community were considered important in the surrounding neighbourhood. Combined, these findings emphasise the importance and complexity associated with designing liveable building, cities and communities, illustrating how adopting a design thinking, human-centred approach will help create sustainable communities that will meet the needs of current and future generations.

Sustainability of a successful health and nutrition program in a remote Aboriginal community

OBJECTIVE: To assess the long term effect of a nutrition program in a remote Aboriginal community (Minjilang). DESIGN: Evaluation of nutritional outcomes over the three years before and the three years after a health and nutrition program that ran from June 1989 to June 1990. Turnover of food items at the community store was used as a measure of dietary intake at Minjilang and a comparison community. SETTING: A community of about 150 Aboriginal people live at Minjilang on Croker Island, 240 km north-east of Darwin. A similar community of about 300 people on another island was used as the comparison. RESULTS: The program produced lasting improvements in dietary intake of most target foods (including fruit, vegetables and wholegrain bread) and nutrients (including folate, ascorbic acid and thiamine). Sugar intake fell in both communities before the program, but the additional decrease in sugar consumption during the program at Minjilang "rebounded" in the next year. Dietary improvements in the comparison community were delayed and smaller than at Minjilang. CONCLUSIONS: The success of the program at Minjilang was linked to an ongoing process of social change, which in turn provided a stimulus for dietary improvement in the comparison community. When Aboriginal people themselves control and maintain ownership of community-based intervention programs, nutritional improvements can be initiated and sustained.

The Tarim picrite-basalt-rhyolite suite, a Permian flood basalt from Northwest China with contrasting rhyolites produced by fractional crystallization and anatexis

We report major and trace element composition, Sr–Nd isotopic and seismological data for a picrite–basalt–rhyolite suite from the northern Tarim uplift (NTU), northwest China. The samples were recovered from 13 boreholes at depths between 5,166 and 6,333 m. The picritic samples have high MgO (14.5–16.8 wt%, volatiles included) enriched in incompatible element and have high 87Sr/86Sr and low 143Nd/144Nd isotopic ratios (εNd (t) = −5.3; Sri = 0.707), resembling the Karoo high-Ti picrites. All the basaltic samples are enriched in TiO2 (2.1–3.2 wt%, volatiles free), have high FeOt abundances (11.27–15.75 wt%, volatiles free), are enriched in incompatible elements and have high Sr and low Nd isotopic ratios (Sri = 0.7049–0.7065; εNd (t) = −4.1 to −0.4). High Nb/La ratios (0.91–1.34) of basalts attest that they are mantle-derived magma with negligible crustal contamination. The rhyolite samples can be subdivided into two coeval groups with overlapping U–Pb zircon ages between 291 ± 4 and 272 ± 2 Ma. Group 1 rhyolites are enriched in Nb and Ta, have similar Nb/La, Nb/U, and Sr–Nd isotopic compositions to the associated basalts, implying that they are formed by fractional crystallization of the basalts. Group 2 rhyolites are depleted in Nb and Ta, have low Nb/La ratios, and have very high Sr and low Nd isotopic ratios, implying that crustal materials have been extensively, if not exclusively, involved in their source. The picrite–basalt–rhyolite suite from the NTU, together with Permian volcanic rocks from elsewhere Tarim basin, constitute a Large Igneous Province (LIP) that is characterized by large areal extent, rapid eruption, OIB-type chemical composition, and eruption of high temperature picritic magma. The Early Permian magmatism, which covered an area >300,000 km2, is therefore named the Tarim Flood Basalt.

Toward understanding social engineering

There is no doubt that social engineering plays a vital role in compromising most security defenses, and in attacks on people, organizations, companies, or even governments. It is the art of deceiving and tricking people to reveal critical information or to perform an action that benefits the attacker in some way. Fraudulent and deceptive people have been using social engineering traps and tactics using information technology such as e-mails, social networks, web sites, and applications to trick victims into obeying them, accepting threats, and falling victim to various crimes and attacks such as phishing, sexual abuse, financial abuse, identity theft, impersonation, physical crime, and many other forms of attack. Although organizations, researchers, practitioners, and lawyers recognize the severe risk of social engineering-based threats, there is a severe lack of understanding and controlling of such threats. One side of the problem is perhaps the unclear concept of social engineering as well as the complexity of understand human behaviors in behaving toward, approaching, accepting, and failing to recognize threats or the deception behind them. The aim of this paper is to explain the definition of social engineering based on the related theories of the many related disciplines such as psychology, sociology, information technology, marketing, and behaviourism. We hope, by this work, to help researchers, practitioners, lawyers, and other decision makers to get a fuller picture of social engineering and, therefore, to open new directions of collaboration toward detecting and controlling it.

Reconstruction of the ancestral marsupial karyotype from comparative gene maps

BACKGROUND: The increasing number of assembled mammalian genomes makes it possible to compare genome organisation across mammalian lineages and reconstruct chromosomes of the ancestral marsupial and therian (marsupial and eutherian) mammals. However, the reconstruction of ancestral genomes requires genome assemblies to be anchored to chromosomes. The recently sequenced tammar wallaby (Macropus eugenii) genome was assembled into over 300,000 contigs. We previously devised an efficient strategy for mapping large evolutionarily conserved blocks in non-model mammals, and applied this to determine the arrangement of conserved blocks on all wallaby chromosomes, thereby permitting comparative maps to be constructed and resolve the long debated issue between a 2n=14 and 2n=22 ancestral marsupial karyotype. RESULTS: We identified large blocks of genes conserved between human and opossum, and mapped genes corresponding to the ends of these blocks by fluorescence in situ hybridization (FISH). A total of 242 genes was assigned to wallaby chromosomes in the present study, bringing the total number of genes mapped to 554 and making it the most densely cytogenetically mapped marsupial genome. We used these gene assignments to construct comparative maps between wallaby and opossum, which uncovered many intrachromosomal rearrangements, particularly for genes found on wallaby chromosomes X and 3. Expanding comparisons to include chicken and human permitted the putative ancestral marsupial (2n=14) and therian mammal (2n=19) karyotypes to be reconstructed. CONCLUSIONS: Our physical mapping data for the tammar wallaby has uncovered the events shaping marsupial genomes and enabled us to predict the ancestral marsupial karyotype, supporting a 2n=14 ancestor. Futhermore, our predicted therian ancestral karyotype has helped to understand the evolution of the ancestral eutherian genome.

Photodissociation of TEMPO-modified peptides: New approaches to radical-directed dissociation of biomolecules

Radical-directed dissociation of gas phase ions is emerging as a powerful and complementary alternative to traditional tandem mass spectrometric techniques for biomolecular structural analysis. Previous studies have identified that coupling of 2-[(2,2,6,6-tetramethylpiperidin-1-oxyl)methyl] benzoic acid (TEMPO-Bz) to the N-terminus of a peptide introduces a labile oxygen-carbon bond that can be selectively activated upon collisional activation to produce a radical ion. Here we demonstrate that structurally-defined peptide radical ions can also be generated upon UV laser photodissociation of the same TEMPO-Bz derivatives in a linear ion-trap mass spectrometer. When subjected to further mass spectrometric analyses, the radical ions formed by a single laser pulse undergo identical dissociations as those formed by collisional activation of the same precursor ion, and can thus be used to derive molecular structure. Mapping the initial radical formation process as a function of photon energy by photodissociation action spectroscopy reveals that photoproduct formation is selective but occurs only in modest yield across the wavelength range (300-220 nm), with the photoproduct yield maximised between 235 and 225 nm. Based on the analysis of a set of model compounds, structural modifications to the TEMPO-Bz derivative are suggested to optimise radical photoproduct yield. Future development of such probes offers the advantage of increased sensitivity and selectivity for radical-directed dissociation. © 2014 the Owner Societies.

A novel, automated nutrition screening system as a predictor of nutritional risk in an oncology day treatment unit (ODTU)

Purpose Paper-based nutrition screening tools can be challenging to implement in the ambulatory oncology setting. The aim of this study was to determine the validity of the Malnutrition Screening Tool (MST) and a novel, automated nutrition screening system compared to a ‘gold standard’ full nutrition assessment using the Patient-Generated Subjective Global Assessment (PG-SGA). Methods An observational, cross-sectional study was conducted in an outpatient oncology day treatment unit (ODTU) within an Australian tertiary health service. Eligibility criteria were as follows: ≥18 years, receiving outpatient anticancer treatment and English literate. Patients self-administered the MST. A dietitian assessed nutritional status using the PGSGA, blinded to the MST score. Automated screening system data were extracted from an electronic oncology prescribing system. This system used weight loss over 3 to 6 weeks prior to the most recent weight record or age-categorised body mass index (BMI) to identify nutritional risk. Sensitivity and specificity against PG-SGA (malnutrition) were calculated using contingency tables and receiver operating curves. Results There were a total of 300 oncology outpatients (51.7 % male, 58.6±13.3 years). The area under the curve (AUC) for weight loss alone was 0.69 with a cut-off value of ≥1 % weight loss yielding 63 % sensitivity and 76.7 % specificity. MST (score ≥2) resulted in 70.6 % sensitivity and 69.5 % specificity, AUC 0.77. Conclusions Both the MST and the automated method fell short of the accepted professional standard for sensitivity (~≥80 %) derived from the PG-SGA. Further investigation into other automated nutrition screening options and the most appropriate parameters available electronically is warranted to support targeted service provision.

Automatic classification of free-text radiology reports to identify limb fractures using machine learning and the SNOMED CT ontology

Objective To develop and evaluate machine learning techniques that identify limb fractures and other abnormalities (e.g. dislocations) from radiology reports. Materials and Methods 99 free-text reports of limb radiology examinations were acquired from an Australian public hospital. Two clinicians were employed to identify fractures and abnormalities from the reports; a third senior clinician resolved disagreements. These assessors found that, of the 99 reports, 48 referred to fractures or abnormalities of limb structures. Automated methods were then used to extract features from these reports that could be useful for their automatic classification. The Naive Bayes classification algorithm and two implementations of the support vector machine algorithm were formally evaluated using cross-fold validation over the 99 reports. Result Results show that the Naive Bayes classifier accurately identifies fractures and other abnormalities from the radiology reports. These results were achieved when extracting stemmed token bigram and negation features, as well as using these features in combination with SNOMED CT concepts related to abnormalities and disorders. The latter feature has not been used in previous works that attempted classifying free-text radiology reports. Discussion Automated classification methods have proven effective at identifying fractures and other abnormalities from radiology reports (F-Measure up to 92.31%). Key to the success of these techniques are features such as stemmed token bigrams, negations, and SNOMED CT concepts associated with morphologic abnormalities and disorders. Conclusion This investigation shows early promising results and future work will further validate and strengthen the proposed approaches.