Lack of microsatellite instability in gastrointestinal stromal tumors

The microsatellite instability (MSI) phenotype may constitute an important biomarker for patient response to immunotherapy, particularly to anti-programmed death-1 inhibitors. MSI is a type of genomic instability caused by a defect in DNA mismatch repair (MMR) proteins, which is present mainly in colorectal cancer and its hereditary form, hereditary nonpolyposis colorectal cancer. Gastrointestinal stromal tumor (GIST) development is associated with activating mutations of KIT proto-oncogene receptor tyrosine kinase (KIT) or platelet-derived growth factor receptor alpha (PDGFRA), which are oncogenes that predict the response to imatinib mesylate. In addition to KIT/PDGFRA mutations, other molecular alterations are important in GIST development. In GISTs, the characterization of the MSI phenotype is scarce and the results are not consensual. The present study aimed to assess MSI in a series of 79 GISTs. The evaluation of MSI was performed by pentaplex polymerase chain reaction comprising five markers, followed by capillary electrophoresis. The expression of MMR proteins was evaluated by immunohistochemistry. Regarding the KIT/PDGFRA/B-Raf proto-oncogene, serine/threonine kinase molecular profile of the 79 GISTs, 83.6% of the tumors possessed KIT mutations, 10.1% had PDGFRA mutations and 6.3% were triple wild-type. The mutated-PDGFRA cases were associated with gastric location and a lower mitotic index compared with KIT-mutated and wild-types, and these patients were more likely to be alive and without cancer. MSI analysis identified 4 cases with instability in one marker, however, additional evaluation of normal tissue and immunohistochemical staining of MMR proteins confirmed their microsatellite-stable nature. The results of the present study indicated that MSI is not involved in GIST tumorigenesis and, therefore, cannot serve as a biomarker to immunotherapy response in GIST.The present study was supported by The Brazilian National Council for Scientific and Technological Development (grant no. 476192/2013-7) and the São Paulo Research Foundation Doctoral Fellowship (grant no. 2013/25787-3).info:eu-repo/semantics/publishedVersio

Microlensing by natural wormholes: theory and simulations

We provide an in depth study of the theoretical peculiarities that arise in effective negative mass lensing, both for the case of a point mass lens and source, and for extended source situations. We describe novel observational signatures arising in the case of a source lensed by a negative mass. We show that a negative mass lens produces total or partial eclipse of the source in the umbra region and also show that the usual Shapiro time delay is replaced with an equivalent time gain. We describe these features both theoretically, as well as through numerical simulations. We provide negative mass microlensing simulations for various intensity profiles and discuss the differences between them. The light curves for microlensing events are presented and contrasted with those due to lensing produced by normal matter. Presence or absence of these features in the observed microlensing events can shed light on the existence of natural wormholes in the Universe.Comment: 16 pages, 24 postscript figures (3 coloured), revtex style, submitted to Phys. Rev.

Might some gamma ray bursts be an observable signature of natural wormholes?

The extragalactic microlensing scenario for natural wormholes is examined. It is shown that the main features of wormhole lensing events upon the light of distant Active Galactic Nuclei (AGNs) are similar to some types of already observed Gamma Ray Bursts (GRBs). Using recent satellite data on GRBs, an upper limit to the negative mass density -- ${\cal O} (10^{-36})$ g cm$^{-3}$ -- under the form of wormhole-like objects is presented.Comment: extended version, additions on GRB physics, background sources and cosmological consequences. Two ps figures. Accpeted for publication in Phys. Rev.

Radio detections towards unidentified variable EGRET sources

Context. A considerable fraction of the -ray sources discovered with the Energetic Gamma-Ray Experiment Telescope (EGRET) remain unidentified. The EGRET sources that have been properly identified are either pulsars or variable sources at both radio and gamma-ray wavelengths. Most of the variable sources are strong radio blazars. However, some low galactic-latitude EGRET sources, with highly variable -ray emission, lack any evident counterpart according to the radio data available until now. Aims. The primary goal of this paper is to identify and characterise the potential radio counterparts of four highly variable -ray sources in the galactic plane through mapping the radio surroundings of the EGRET confidence contours and determining the variable radio sources in the field whenever possible. Methods. We have carried out a radio exploration of the fields of the selected EGRET sources using the Giant Metrewave Radio Telescope (GMRT) interferometer at 21 cm wavelength, with pointings being separated by months. Results. We detected a total of 151 radio sources. Among them, we identified a few radio sources whose flux density has apparently changed on timescales of months. Despite the limitations of our search, their possible variability makes these objects a top-priority target for multiwavelength studies of the potential counterparts of highly variable, unidentified gamma-ray sources.Facultad de Ciencias Astronómicas y GeofísicasInstituto Argentino de Radioastronomí

Phylogenetic and functional diversity of metagenomic libraries of phenol degrading sludge from petroleum refinery wastewater treatment system

In petrochemical refinery wastewater treatment plants (WWTP), different concentrations of pollutant compounds are received daily in the influent stream, including significant amounts of phenolic compounds, creating propitious conditions for the development of particular microorganisms that can rapidly adapt to such environment. In the present work, the microbial sludge from a refinery WWTP was enriched for phenol, cloned into fosmid vectors and pyrosequenced. The fosmid libraries yielded 13,200 clones and a comprehensive bioinformatic analysis of the sequence data set revealed a complex and diverse bacterial community in the phenol degrading sludge. The phylogenetic analyses using MEGAN in combination with RDP classifier showed a massive predominance of Proteobacteria, represented mostly by the genera Diaphorobacter, Pseudomonas, Thauera and Comamonas. The functional classification of phenol degrading sludge sequence data set generated by MG-RAST showed the wide metabolic diversity of the microbial sludge, with a high percentage of genes involved in the aerobic and anaerobic degradation of phenol and derivatives. In addition, genes related to the metabolism of many other organic and xenobiotic compounds, such as toluene, biphenyl, naphthalene and benzoate, were found. Results gathered herein demonstrated that the phenol degrading sludge has complex phylogenetic and functional diversities, showing the potential of such community to degrade several pollutant compounds. This microbiota is likely to represent a rich resource of versatile and unknown enzymes which may be exploited for biotechnological processes such as bioremediation

A hypoperfusion context may aid to interpret hyperlactatemia in sepsis-3 septic shock patients: a proof-of-concept study

__Background:__ Persistent hyperlactatemia is particularly difficult to interpret in septic shock. Besides hypoperfusion, adrenergic-driven lactate production and impaired lactate clearance are important contributors. However, clinical recognition of different sources of hyperlactatemia is unfortunately not a common practice and patients are treated with the same strategy despite the risk of over-resuscitation in some. Indeed, pursuing additional resuscitation in non-hypoperfusion-related cases might lead to the toxicity of fluid overload and vasoactive drugs. We hypothesized that two different clinical patterns can be recognized in septic shock patients through a multimodal perfusion monitoring. Hyperlactatemic patients with a hypoperfusion context probably represent a more severe acute circulatory dysfunction, and the absence of a hypoperfusion context is eventually associated with a good outcome. We performed a retrospective analysis of a database of septic shock patients with persistent hyperlactatemia after initial resuscitation. __Results:__ We defined hypoperfusion context by the presence of a ScvO2 < 70%, or a P(cv-a)CO2 ≥6 mmHg, or a CRT ≥4 s together with hyperlactatemia. Ninety patients were included, of whom seventy exhibited a hypoperfusion-related pattern and 20 did not. Although lactate values were comparable at baseline (4.8 ± 2.8 vs. 4.7 ± 3.7 mmol/L), patients with a hypoperfusion context exhibited a more severe circulatory dysfunction with higher vasopressor requirements, and a trend to longer mechanical ventilation days, ICU stay, and more rescue therapies. Only one of the 20 hyperlactatemic patients without a hypoperfusion context died (5%) compared to 11 of the 70 with hypoperfusion-related hyperlactatemia (16%). __Conclusions:__ Two different clinical patterns among hyperlactatemic septic shock patients may be identified according to hypoperfusion context. Patients with hyperlactatemia plus low ScvO2, or high P(cv-a)CO2, or high CRT values exhibited a more severe circulatory dysfunction. This provides a starting point to launch further prospective studies to confirm if this approach can lead to a more selective resuscitation strategy

Radio detections towards unidentified variable EGRET sources

Context. A considerable fraction of the -ray sources discovered with the Energetic Gamma-Ray Experiment Telescope (EGRET) remain unidentified. The EGRET sources that have been properly identified are either pulsars or variable sources at both radio and gamma-ray wavelengths. Most of the variable sources are strong radio blazars. However, some low galactic-latitude EGRET sources, with highly variable -ray emission, lack any evident counterpart according to the radio data available until now. Aims. The primary goal of this paper is to identify and characterise the potential radio counterparts of four highly variable -ray sources in the galactic plane through mapping the radio surroundings of the EGRET confidence contours and determining the variable radio sources in the field whenever possible. Methods. We have carried out a radio exploration of the fields of the selected EGRET sources using the Giant Metrewave Radio Telescope (GMRT) interferometer at 21 cm wavelength, with pointings being separated by months. Results. We detected a total of 151 radio sources. Among them, we identified a few radio sources whose flux density has apparently changed on timescales of months. Despite the limitations of our search, their possible variability makes these objects a top-priority target for multiwavelength studies of the potential counterparts of highly variable, unidentified gamma-ray sources.Facultad de Ciencias Astronómicas y GeofísicasInstituto Argentino de Radioastronomí

Is the Supernova Remnant RX J1713.7-3946 a Hadronic Cosmic Ray Accelerator ?

The non-thermal supernova remnant RX J1713.7-3946 (G347.3-0.5) has recently been shown to be a site of cosmic ray (CR) electron acceleration to TeV energies (Muraishi et al. 2000). Here we present evidence that this remnant is also accelerating CR nuclei. Such nuclei can interact with ambient interstellar gas to produce high energy gamma-rays via the decay of neutral pions. We associate the unidentified EGRET GeV gamma- ray source 3EG J1714-3857 with a massive (~3*10 5 Mo) and dense (~500 nucleons cm -3) molecular cloud interacting with RX J1713.7-3946. Direct evidence for such interaction is provided by observations of the lowest two rotational transitions of CO in the cloud; as in other clear cases of interaction, the CO(J=2-1)/CO(J=1-0) ratio is significantly enhanced. Since the cloud is of low radio and X-ray brightness, CR electrons cannot be responsible for the bulk of its GeV emission there. A picture thus emerges where both electrons and nuclei are being accelerated by the SNR: whereas the CR electrons dominate the local non-thermal radio, X-ray and TeV emission, the shock accelerated CR protons and ions (hadrons) are revealed through their interactions in the adjacent massive cloud. Such a scenario had been anticipated by Aharonian, Drury and Volk (1994).Comment: 15 pages, 2 low-resolution figures, submitted to ApJL Aug 10, 2001; this version includes referee's suggestion

Testing the Correlation of Ultra-High Energy Cosmic Rays with High Redshift Sources

We study the correlation between compact radio quasars or 3EG gamma-ray blazars and the arrival directions of cosmic rays above 10^19 eV using an updated list of air shower detections. Our Monte Carlo simulations reveal no significant correlations above random and some previous positive results appear to be an effect of the small sample size. Consequently, unless somehow severely deflected, there is no evidence for ultra-high energy cosmic ray primaries being new particles or particles with new interactions beyond the electroweak scale, produced in high-redshift active galactic nuclei.Comment: 5 latex pages, uses revtex, no figures. revised and expanded versio