International Climate Efforts Beyond 2012: A Survey of Approaches

Provides an overview of key issues in the design and negotiation of future international climate efforts and describes how various proposals seek to address them. Outlines criteria for assessing different options from a policy and a political perspective

The Foreign Account Tax Compliance Act: The Solution or the Problem?

Tax evasion has been happening for decades, but after the highly publicized cases with two foreign banks, LGT and UBS, the United States (US) is cracking down on tax evaders. The latest addition to the Internal Revenue Service (IRS)’s repertoire of enforcement tools is the Foreign Account Tax Compliance Act, otherwise known as FATCA. The Act was enacted to incentivize tax information release by foreign financial institutions (FFIs) who would otherwise face a 30% withholding tax on any US source income. The question was whether or not the design of the Act and its implementation successfully met this goal. This paper explores the history leading up to FATCA’s creation, beginning from the basic data underlying tax evasion. With the US losing approximately $100 billion a year of tax revenue, the IRS is keen on reducing the money flow out of the US. It will dig deeper into the facts of the LGT and UBS cases which led to Congress’s realization that their other enforcement mechanisms were not sufficient and describe FATCA’s unintended impact. Through researching articles on the predicted impact of FATCA, surveys of FFIs, testimonials from US citizens, this paper will explain how FATCA has unfortunately detrimentally impacted FFIs and US citizens living abroad

Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer.

Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance

Coccolithophorid calcium carbonate dissolution in surface waters

The role of calcifying organisms in the ocean biogeochemistry has been receiving increasing attention since CO2-related global change issues such as ocean acidification were pointed out by the scientific community. The implications of changing oceanic pH in modifying ecosystems dominated by planktonic calcifiers have been shown by mesocosm and laboratory experiments based on CO2 manipulations. The major concern of such experiments focussed on variations in the rates of ecosystem primary production and calcification due to changes in algal physiology or specific composition. Our results, from an interdisciplinary survey of coccolithophore-dominated blooms in the northern Bay of Biscay (NE Atlantic), suggest that biogenic calcite dissolution is occurring in the photic zone where surface waters are oversaturated with respect to calcite. The dissolution of CaCO3 in surface waters, evidenced by scanning electron microscopy observations, has an impact on the preservation and export of carbon in coccolithophore-dominated ecosystems and on the exchange of CO2 across the ocean-atmosphere interface. Both aspects of suspended calcite concentration reduction in natural environments (lower rates of production or dissolution) could be considered as a perturbation of the oceanic carbon cycle. We aim at presenting here a biogeochemical description of processes, including integrated primary production, calcification, and parameters such as transparent exopolymer particles concentration and particulate inorganic carbon profiles, during field studies. A mechanism for calcite dissolution, based on biological activity in microenvironments (including grazing, bacterial respiration and DMS production) is presented as a conceptual model in coccolithophore blooms

Growth Arrest of BCR-ABL Positive Cells with a Sequence-Specific Polyamide-Chlorambucil Conjugate

Chronic myeloid leukemia (CML) is characterized by the presence of a constitutively active Abl kinase, which is the product of a chimeric BCR-ABL gene, caused by the genetic translocation known as the Philadelphia chromosome. Imatinib, a selective inhibitor of the Bcr-Abl tyrosine kinase, has significantly improved the clinical outcome of patients with CML. However, subsets of patients lose their response to treatment through the emergence of imatinib-resistant cells, and imatinib treatment is less durable for patients with late stage CML. Although alternative Bcr-Abl tyrosine kinase inhibitors have been developed to overcome drug resistance, a cocktail therapy of different kinase inhibitors and additional chemotherapeutics may be needed for complete remission of CML in some cases. Chlorambucil has been used for treatment of B cell chronic lymphocytic leukemia, non-Hodgkin's and Hodgkin's disease. Here we report that a DNA sequence-specific pyrrole-imidazole polyamide-chlorambucil conjugate, 1R-Chl, causes growth arrest of cells harboring both unmutated BCR-ABL and three imatinib resistant strains. 1R-Chl also displays selective toxicities against activated lymphocytes and a high dose tolerance in a murine model

Glycaemic control in people with type 2 diabetes mellitus during and after cancer treatment: A systematic review and meta-analysis

Background Cancer and Diabetes Mellitus (DM) are leading causes of death worldwide and the prevalence of both is escalating. People with co-morbid cancer and DM have increased morbidity and premature mortality compared with cancer patients with no DM. The reasons for this are likely to be multifaceted but will include the impact of hypo/hyperglycaemia and diabetes therapies on cancer treatment and disease progression. A useful step toward addressing this disparity in treatment outcomes is to establish the impact of cancer treatment on diabetes control. Aim The aim of this review is to identify and analyse current evidence reporting glycaemic control (HbA1c) during and after cancer treatment. Methods Systematic searches of published quantitative research relating to comorbid cancer and type 2 diabetes mellitus were conducted using databases, including Medline, Embase, PsychINFO, CINAHL and Web of Science (February 2017). Full text publications were eligible for inclusion if they: were quantitative, published in English language, investigated the effects of cancer treatment on glycaemic control, reported HbA1c (%/mmols/mol) and included adult populations with diabetes. Means, standard deviations and sample sizes were extracted from each paper; missing standard deviations were imputed. The completed datasets were analysed using a random effects model. A mixed-effects analysis was undertaken to calculate mean HbA1c (%/mmols/mol) change over three time periods compared to baseline. Results The available literature exploring glycaemic control post-diagnosis was mixed. There was increased risk of poor glycaemic control during this time if studies of surgical treatment for gastric cancer are excluded, with significant differences between baseline and 12 months (p < 0.001) and baseline and 24 months (p = 0.002). Conclusion We found some evidence to support the contention that glycaemic control during and/or after non-surgical cancer treatment is worsened, and the reasons are not well defined in individual studies. Future studies should consider the reasons why this is the case

An evaluation of custom microarray applications: the oligonucleotide design challenge

The increase in feature resolution and the availability of multipack formats from microarray providers has opened the way to various custom genomic applications. However, oligonucleotide design and selection remains a bottleneck of the microarray workflow. Several tools are available to perform this work, and choosing the best one is not an easy task, nor are the choices obvious. Here we review the oligonucleotide design field to help users make their choice. We have first performed a comparative evaluation of the available solutions based on a set of criteria including: ease of installation, user-friendly access, the number of parameters and settings available. In a second step, we chose to submit two real cases to a selection of programs. Finally, we used a set of tests for the in silico benchmark of the oligo sets obtained from each type of software. We show that the design software must be selected according to the goal of the scientist, depending on factors such as the organism used, the number of probes required and their localization on the target sequence. The present work provides keys to the choice of the most relevant software, according to the various parameters we tested