Modulation of PKM alternative splicing by PTBP1 promotes gemcitabine resistance in pancreatic cancer cells

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and incurable disease. Poor prognosis is due to multiple reasons, including acquisition of resistance to gemcitabine, the first-line chemotherapeutic approach. Thus, there is a strong need for novel therapies, targeting more directly the molecular aberrations of this disease. We found that chronic exposure of PDAC cells to gemcitabine selected a subpopulation of cells that are drug-resistant (DR-PDAC cells). Importantly, alternative splicing (AS) of the pyruvate kinase gene (PKM) was differentially modulated in DR-PDAC cells, resulting in promotion of the cancer-related PKM2 isoform, whose high expression also correlated with shorter recurrence-free survival in PDAC patients. Switching PKM splicing by antisense oligonucleotides to favor the alternative PKM1 variant rescued sensitivity of DR-PDAC cells to gemcitabine and cisplatin, suggesting that PKM2 expression is required to withstand drug-induced genotoxic stress. Mechanistically, upregulation of the polypyrimidine-tract binding protein (PTBP1), a key modulator of PKM splicing, correlated with PKM2 expression in DR-PDAC cell lines. PTBP1 was recruited more efficiently to PKM pre-mRNA in DR- than in parental PDAC cells. Accordingly, knockdown of PTBP1 in DR-PDAC cells reduced its recruitment to the PKM pre-mRNA, promoted splicing of the PKM1 variant and abolished drug resistance. Thus, chronic exposure to gemcitabine leads to upregulation of PTBP1 and modulation of PKM AS in PDAC cells, conferring resistance to the drug. These findings point to PKM2 and PTBP1 as new potential therapeutic targets to improve response of PDAC to chemotherapy.Oncogene advance online publication, 3 August 2015; doi:10.1038/onc.2015.270

Toward the next generation of research into small area effects on health : a synthesis of multilevel investigations published since July 1998.

To map out area effects on health research, this study had the following aims: (1) to inventory multilevel investigations of area effects on self rated health, cardiovascular diseases and risk factors, and mortality among adults; (2) to describe and critically discuss methodological approaches employed and results observed; and (3) to formulate selected recommendations for advancing the study of area effects on health. Overall, 86 studies were inventoried. Although several innovative methodological approaches and analytical designs were found, small areas are most often operationalised using administrative and statistical spatial units. Most studies used indicators of area socioeconomic status derived from censuses, and few provided information on the validity and reliability of measures of exposures. A consistent finding was that a significant portion of the variation in health is associated with area context independently of individual characteristics. Area effects on health, although significant in most studies, often depend on the health outcome studied, the measure of area exposure used, and the spatial scale at which associations are examined

A simple and low-power optical limiter for multi-GHz pulse trains

We study the limiting-amplification capability of a saturated Semiconductor Optical Amplifier (SOA) followed by an optical band-pass filter. We experimentally demonstrate that this simple optical circuit can be effectively exploited to realize a low-power optical limiter for amplitude-modulated pulse trains at multi-GHz repetition rate. We report very large amplitude-modulation-reduction factors for the case of 20 and 40 GHz pulse trains that are super-imposed with modulating frequencies ranging from 100kHz to several GHz. (C) 2007 Optical Society of America

A simple and low-power optical limiter for multi-GHz pulse trains

We study the limiting-amplification capability of a saturated Semiconductor Optical Amplifier (SOA) followed by an optical band-pass filter. We experimentally demonstrate that this simple optical circuit can be effectively exploited to realize a low-power optical limiter for amplitudemodulated pulse trains at multi-GHz repetition rate. We report very large amplitude-modulation-reduction factors for the case of 20 and 40 GHz pulse trains that are super-imposed with modulating frequencies ranging from 100 kHz to several GHz

Representations of spectral coordinates in FITS

Greisen & Calabretta describe a generalized method for specifying the coordinates of FITS data samples. Following that general method, Calabretta & Greisen describe detailed conventions for defining celestial coordinates as they are projected onto a two-dimensional plane. The present paper extends the discussion to the spectral coordinates of wavelength, frequency, and velocity. World coordinate functions are defined for spectral axes sampled linearly in wavelength, frequency, or velocity, linearly in the logarithm of wavelength or frequency, as projected by ideal dispersing elements, and as specified by a lookup table.Comment: 25 pages, 5 figure