Convergent Sequences of Dense Graphs I: Subgraph Frequencies, Metric Properties and Testing

We consider sequences of graphs and define various notions of convergence related to these sequences: ``left convergence'' defined in terms of the densities of homomorphisms from small graphs into the graphs of the sequence, and ``right convergence'' defined in terms of the densities of homomorphisms from the graphs of the sequence into small graphs; and convergence in a suitably defined metric. In Part I of this series, we show that left convergence is equivalent to convergence in metric, both for simple graphs, and for graphs with nodeweights and edgeweights. One of the main steps here is the introduction of a cut-distance comparing graphs, not necessarily of the same size. We also show how these notions of convergence provide natural formulations of Szemeredi partitions, sampling and testing of large graphs.Comment: 57 pages. See also http://research.microsoft.com/~borgs/. This version differs from an earlier version from May 2006 in the organization of the sections, but is otherwise almost identica

Final countdown for biodiversity hotspots

Most of Earth's biodiversity is found in 36 biodiversity hotspots, yet less than 10% natural intact vegetation remains. We calculated models projecting the future state of most of these hotspots for the year 2050, based on future climatic and agroeconomic pressure. Our models project an increasing demand for agricultural land resulting in the conversion of >50% of remaining natural intact vegetation in about one third of all hotspots, and in 2-6 hotspots resulting from climatic pressure. This confirms that, in the short term, habitat loss is of greater concern than climate change for hotspots and their biodiversity. Hotspots are most severely threatened in tropical Africa and parts of Asia, where demographic pressure and the demand for agricultural land is highest. The speed and magnitude of pristine habitat loss is, according to our models, much greater than previously shown when combining both scenarios on future climatic and agroeconomic pressure

The school environment and adolescent physical activity and sedentary behaviour : A mixed-studies systematic review

There is increasing academic and policy interest in interventions aiming to promote young people's health by ensuring that the school environment supports healthy behaviours. The purpose of this review was to summarize the current evidence on school-based policy, physical and social-environmental influences on adolescent physical activity and sedentary behaviour. Electronic databases were searched to identify studies that (1) involved healthy adolescents (11-18years old), (2) investigated school-environmental influences and (3) reported a physical activity and/or sedentary behaviour outcome or theme. Findings were synthesized using a non-quantitative synthesis and thematic analysis. Ninety-three papers of mixed methodological quality were included. A range of school-based policy (e.g. break time length), physical (e.g. facilities) and social-environmental (e.g. teacher behaviours) factors were associated with adolescent physical activity, with limited research on sedentary behaviour. The mixed-studies synthesis revealed the importance of specific activity settings (type and location) and intramural sport opportunities for all students. Important physical education-related factors were a mastery-oriented motivational climate and autonomy supportive teaching behaviours. Qualitative evidence highlighted the influence of the wider school climate and shed light on complexities of the associations observed in the quantitative literature. This review identifies future research needs and discusses potential intervention approaches to be considered

Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer.

Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest, possibly because of dynamic changes in cellular signaling that drive resistance and limit drug efficacy. Using a quantitative chemoproteomics approach, we mapped kinome dynamics in response to inhibitors of this pathway and identified signaling changes that correlate with drug sensitivity. Maintenance of AURKA after drug treatment was associated with resistance in breast cancer models. Incomplete inhibition of AURKA was a common source of therapy failure, and combinations of PI3K, AKT or mTOR inhibitors with the AURKA inhibitor MLN8237 were highly synergistic and durably suppressed mTOR signaling, resulting in apoptosis and tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of targeted therapies and reveals new drug combinations that may unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer

Cell phone-supported cognitive behavioural therapy for anxiety disorders: a protocol for effectiveness studies in frontline settings

The resulting protocol (NCT01205191 at clinicaltrials.gov) for use in frontline clinical practice in which effectiveness, adherence, and the role of the therapists are analyzed, provides evidence for what are truly valuable cell phone-supported CBT treatments and guidance for the broader introduction of CBT in health services.Original Publication:Joakim Ekberg, Toomas Timpka, Magnus Bång, Anders Fröberg, Karin Halje and Henrik Eriksson, Cell phone-supported cognitive behavioural therapy for anxiety disorders: a protocol for effectiveness studies in frontline settings., 2011, BMC medical research methodology, (11), 3.http://dx.doi.org/10.1186/1471-2288-11-3Copyright: BioMed Centralhttp://www.biomedcentral.com

The willingness of final year medical and dental students to perform bystander cardiopulmonary resuscitation in an Asian community

Background Despite the importance of early effective chest compressions to improve the chance of survival of an out-of-hospital cardiac arrest victim, it is still largely unknown how willing our Malaysian population is to perform bystander cardiopulmonary resuscitation (CPR). Aims We conducted a voluntary, anonymous self-administered questionnaire survey of a group of 164 final year medical students and 60 final year dental students to unravel their attitudes towards performing bystander CPR. Methods Using a 4-point Likert scale of “definitely yes,” “probably yes,” “probably no,” and “definitely no,” the students were asked to rate their willingness to perform bystander CPR under three categories: chest compressions with mouth-to-mouth ventilation (CC + MMV), chest compressions with mask-to-mouth ventilation (CC + PMV), and chest compressions only (CC). Under each category, the students were given ten hypothetical victim scenarios. Categorical data analysis was done using the McNemar test, chi-square test, and Fisher exact test where appropriate. For selected analysis, “definitely yes” and “probably yes” were recoded as a “positive response.” Results Generally, we found that only 51.4% of the medical and 45.5% of the dental students are willing to perform bystander CPR. When analyzed under different hypothetical scenarios, we found that, except for the scenario where the victim is their own family member, all other scenarios showed a dismally low rate of positive responses in the category of CC + MMV, but their willingness was significantly improved under the CC + PMV and CC categories. Conclusion This study shows that there are unique sociocultural factors that contribute to the reluctance of our students to perform CC + MMV. Keywords Cardiopulmonary resuscitation Mouth-to-mouth resuscitation Basic cardiac life support Asian communit

Early Detection of Erlotinib Treatment Response in NSCLC by 3′-Deoxy-3′-[18F]-Fluoro-L-Thymidine ([18F]FLT) Positron Emission Tomography (PET)

Background: Inhibition of the epidermal growth factor receptor (EGFR) has shown clinical success in patients with advanced non-small cell lung cancer (NSCLC). Somatic mutations of EGFR were found in lung adenocarcinoma that lead to exquisite dependency on EGFR signaling; thus patients with EGFR-mutant tumors are at high chance of response to EGFR inhibitors. However, imaging approaches affording early identification of tumor response in EGFR-dependent carcinomas have so far been lacking. Methodology/Principal Findings: We performed a systematic comparison of 3′-Deoxy-3′-[$^{18}F$]-fluoro-L-thymidine ([$^{18}F$]FLT) and 2-[$^{18}F$]-fluoro-2-deoxy-D-glucose ([$^{18}F$]FDG) positron emission tomography (PET) for their potential to identify response to EGFR inhibitors in a model of EGFR-dependent lung cancer early after treatment initiation. While erlotinib-sensitive tumors exhibited a striking and reproducible decrease in [$^{18}F$]FLT uptake after only two days of treatment, [$^{18}F$]FDG PET based imaging revealed no consistent reduction in tumor glucose uptake. In sensitive tumors, a decrease in [$^{18}F$]FLT PET but not [$^{18}F$]FDG PET uptake correlated with cell cycle arrest and induction of apoptosis. The reduction in [$^{18}F$]FLT PET signal at day 2 translated into dramatic tumor shrinkage four days later. Furthermore, the specificity of our results is confirmed by the complete lack of [$^{18}F$]FLT PET response of tumors expressing the T790M erlotinib resistance mutation of EGFR. Conclusions: [$^{18}F$]FLT PET enables robust identification of erlotinib response in EGFR-dependent tumors at a very early stage. [$^{18}F$]FLT PET imaging may represent an appropriate method for early prediction of response to EGFR TKI treatment in patients with NSCLC

Prenylation Inhibition-Induced Cell Death in Melanoma: Reduced Sensitivity in BRAF Mutant/PTEN Wild-Type Melanoma Cells.

While targeted therapy brought a new era in the treatment of BRAF mutant melanoma, therapeutic options for non-BRAF mutant cases are still limited. In order to explore the antitumor activity of prenylation inhibition we investigated the response to zoledronic acid treatment in thirteen human melanoma cell lines with known BRAF, NRAS and PTEN mutational status. Effect of zoledronic acid on proliferation, clonogenic potential, apoptosis and migration of melanoma cells as well as the activation of downstream elements of the RAS/RAF pathway were investigated in vitro with SRB, TUNEL and PARP cleavage assays and videomicroscopy and immunoblot measurements, respectively. Subcutaneous and spleen-to-liver colonization xenograft mouse models were used to evaluate the influence of zoledronic acid treatment on primary and disseminated tumor growth of melanoma cells in vivo. Zoledronic acid more efficiently decreased short-term in vitro viability in NRAS mutant cells when compared to BRAF mutant and BRAF/NRAS wild-type cells. In line with this finding, following treatment decreased activation of ribosomal protein S6 was found in NRAS mutant cells. Zoledronic acid demonstrated no significant synergism in cell viability inhibition or apoptosis induction with cisplatin or DTIC treatment in vitro. Importantly, zoledronic acid could inhibit clonogenic growth in the majority of melanoma cell lines except in the three BRAF mutant but PTEN wild-type melanoma lines. A similar pattern was observed in apoptosis induction experiments. In vivo zoledronic acid did not inhibit the subcutaneous growth or spleen-to-liver colonization of melanoma cells. Altogether our data demonstrates that prenylation inhibition may be a novel therapeutic approach in NRAS mutant melanoma. Nevertheless, we also demonstrated that therapeutic sensitivity might be influenced by the PTEN status of BRAF mutant melanoma cells. However, further investigations are needed to identify drugs that have appropriate pharmacological properties to efficiently target prenylation in melanoma cells

Inhibitor-Sensitive FGFR1 Amplification in Human Non-Small Cell Lung Cancer

Background Squamous cell lung carcinomas account for approximately 25% of new lung carcinoma cases and 40,000 deaths per year in the United States. Although there are multiple genomically targeted therapies for lung adenocarcinoma, none has yet been reported in squamous cell lung carcinoma. Methodology/Principal Findings Using SNP array analysis, we found that a region of chromosome segment 8p11-12 containing three genes–WHSC1L1, LETM2, and FGFR1–is amplified in 3% of lung adenocarcinomas and 21% of squamous cell lung carcinomas. Furthermore, we demonstrated that a non-small cell lung carcinoma cell line harboring focal amplification of FGFR1 is dependent on FGFR1 activity for cell growth, as treatment of this cell line either with FGFR1-specific shRNAs or with FGFR small molecule enzymatic inhibitors leads to cell growth inhibition. Conclusions/Significance These studies show that FGFR1 amplification is common in squamous cell lung cancer, and that FGFR1 may represent a promising therapeutic target in non-small cell lung cancer.Novartis Pharmaceuticals CorporationAmerican Lung AssociationUniting Against Lung CancerSara Thomas Monopoli FundSeaman FoundationIndia. Dept. of BiotechnologyNational Lung Cancer Partnershi

Benchmarking of Mutation Diagnostics in Clinical Lung Cancer Specimens

Treatment of EGFR-mutant non-small cell lung cancer patients with the tyrosine kinase inhibitors erlotinib or gefitinib results in high response rates and prolonged progression-free survival. Despite the development of sensitive mutation detection approaches, a thorough validation of these in a clinical setting has so far been lacking. We performed, in a clinical setting, a systematic validation of dideoxy ‘Sanger’ sequencing and pyrosequencing against massively parallel sequencing as one of the most sensitive mutation detection technologies available. Mutational annotation of clinical lung tumor samples revealed that of all patients with a confirmed response to EGFR inhibition, only massively parallel sequencing detected all relevant mutations. By contrast, dideoxy sequencing missed four responders and pyrosequencing missed two responders, indicating a dramatic lack of sensitivity of dideoxy sequencing, which is widely applied for this purpose. Furthermore, precise quantification of mutant alleles revealed a low correlation (r2 = 0.27) of histopathological estimates of tumor content and frequency of mutant alleles, thereby questioning the use of histopathology for stratification of specimens for individual analytical procedures. Our results suggest that enhanced analytical sensitivity is critically required to correctly identify patients responding to EGFR inhibition. More broadly, our results emphasize the need for thorough evaluation of all mutation detection approaches against massively parallel sequencing as a prerequisite for any clinical implementation