632 research outputs found
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Chemotherapy for locally advanced and metastatic pulmonary carcinoid tumors
Objectives
The optimal management of locally advanced and metastatic pulmonary carcinoid tumors remains to be determined.
Materials and methods
A retrospective review was conducted on patients with typical and atypical pulmonary carcinoid tumors treated at our institutions between 1990 and 2012.
Results
300 patients were identified with pulmonary carcinoid, (80 patients with atypical carcinoid), of whom 29 presented with metastatic disease (16 atypical). Of evaluable patients, 26 (41%) with stages I–III atypical carcinoid tumors recurred at a median time of 3.7 years (range, 0.4–32), compared to 3 (1%) patients with typical carcinoid (range, 8–12.3). 39 patients were treated with chemotherapy, including 30 patients with metastatic disease (27 atypical), and 7 patients were treated with adjuvant platinum–etoposide chemoradiation (6 atypical, 1 typical, 6 stage IIIA, 1 stage IIB). At a median follow-up of 2 years there were 2 recurrences in the 7 patients receiving adjuvant treatment. Median survival after diagnosis of metastatic disease for patients with atypical pulmonary carcinoid was 3.3 years with a 5-year survival of 24%. Treatment regimens showing efficacy in pulmonary carcinoid include 15 patients treated with octreotide-based therapies (10% response rate (RR), 70% disease control rate (DCR), 15 month median progression-free survival (PFS)), 13 patients treated with etoposide + platinum (23% RR, 69% DCR, 7 month median PFS), and 14 patients treated with temozolomide-based therapies (14% RR, 57% DCR, 10 month median PFS). 8 of 10 patients with octreotide-avid disease treated with an octreotide-based regimen experienced disease control (1 partial response, 7 stable disease) for a median of 18 months (range 6–72 months).
Conclusions
These results support our previous finding that a subset of pulmonary carcinoid tumors are responsive to chemotherapy
An evolutionary driver of interspersed segmental duplications in primates
Background
The complex interspersed pattern of segmental duplications in humans is responsible for rearrangements associated with neurodevelopmental disease, including the emergence of novel genes important in human brain evolution. We investigate the evolution of LCR16a, a putative driver of this phenomenon that encodes one of the most rapidly evolving human–ape gene families, nuclear pore interacting protein (NPIP).
Results
Comparative analysis shows that LCR16a has independently expanded in five primate lineages over the last 35 million years of primate evolution. The expansions are associated with independent lineage-specific segmental duplications flanking LCR16a leading to the emergence of large interspersed duplication blocks at non-orthologous chromosomal locations in each primate lineage. The intron-exon structure of the NPIP gene family has changed dramatically throughout primate evolution with different branches showing characteristic gene models yet maintaining an open reading frame. In the African ape lineage, we detect signatures of positive selection that occurred after a transition to more ubiquitous expression among great ape tissues when compared to Old World and New World monkeys. Mouse transgenic experiments from baboon and human genomic loci confirm these expression differences and suggest that the broader ape expression pattern arose due to mutational changes that emerged in cis.
Conclusions
LCR16a promotes serial interspersed duplications and creates hotspots of genomic instability that appear to be an ancient property of primate genomes. Dramatic changes to NPIP gene structure and altered tissue expression preceded major bouts of positive selection in the African ape lineage, suggestive of a gene undergoing strong adaptive evolution
Genomic Signatures of Strain Selection and Enhancement in Bacillus atrophaeus var. globigii, a Historical Biowarfare Simulant
(BG) as a simulant for biological warfare (BW) agents, knowledge of its genome composition is limited. Furthermore, the ability to differentiate signatures of deliberate adaptation and selection from natural variation is lacking for most bacterial agents. We characterized a lineage of BGwith a long history of use as a simulant for BW operations, focusing on classical bacteriological markers, metabolic profiling and whole-genome shotgun sequencing (WGS). on the nucleotide level. WGS of variants revealed that several strains were mixed but highly related populations and uncovered a progressive accumulation of mutations among the “military” isolates. Metabolic profiling and microscopic examination of bacterial cultures revealed enhanced growth of “military” isolates on lactate-containing media, and showed that the “military” strains exhibited a hypersporulating phenotype.Our analysis revealed the genomic and phenotypic signatures of strain adaptation and deliberate selection for traits that were desirable in a simulant organism. Together, these results demonstrate the power of whole-genome and modern systems-level approaches to characterize microbial lineages to develop and validate forensic markers for strain discrimination and reveal signatures of deliberate adaptation
The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe
The preponderance of matter over antimatter in the early Universe, the
dynamics of the supernova bursts that produced the heavy elements necessary for
life and whether protons eventually decay --- these mysteries at the forefront
of particle physics and astrophysics are key to understanding the early
evolution of our Universe, its current state and its eventual fate. The
Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed
plan for a world-class experiment dedicated to addressing these questions. LBNE
is conceived around three central components: (1) a new, high-intensity
neutrino source generated from a megawatt-class proton accelerator at Fermi
National Accelerator Laboratory, (2) a near neutrino detector just downstream
of the source, and (3) a massive liquid argon time-projection chamber deployed
as a far detector deep underground at the Sanford Underground Research
Facility. This facility, located at the site of the former Homestake Mine in
Lead, South Dakota, is approximately 1,300 km from the neutrino source at
Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino
charge-parity symmetry violation and mass ordering effects. This ambitious yet
cost-effective design incorporates scalability and flexibility and can
accommodate a variety of upgrades and contributions. With its exceptional
combination of experimental configuration, technical capabilities, and
potential for transformative discoveries, LBNE promises to be a vital facility
for the field of particle physics worldwide, providing physicists from around
the globe with opportunities to collaborate in a twenty to thirty year program
of exciting science. In this document we provide a comprehensive overview of
LBNE's scientific objectives, its place in the landscape of neutrino physics
worldwide, the technologies it will incorporate and the capabilities it will
possess.Comment: Major update of previous version. This is the reference document for
LBNE science program and current status. Chapters 1, 3, and 9 provide a
comprehensive overview of LBNE's scientific objectives, its place in the
landscape of neutrino physics worldwide, the technologies it will incorporate
and the capabilities it will possess. 288 pages, 116 figure
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Multi-institutional Oncogenic Driver Mutation Analysis in Lung Adenocarcinoma: The Lung Cancer Mutation Consortium Experience
Introduction
Molecular genetic analyses of lung adenocarcinoma have recently become standard of care for treatment selection. The Lung Cancer Mutation Consortium was formed to enable collaborative multi-institutional analyses of 10 potential oncogenic driver mutations. Technical aspects of testing, and clinicopathologic correlations are presented.
Methods
Mutation testing in at least one of 8 genes (EGFR, KRAS, ERBB2, AKT1, BRAF, MEK1, NRAS, PIK3CA) using SNaPshot, mass spectrometry, Sanger sequencing +/− PNA and/or sizing assays, along with ALK and/or MET FISH were performed in 6 labs on 1007 patients from 14 institutions.
Results
1007 specimens had mutation analysis performed, and 733 specimens had all 10 genes analyzed. Mutation identification rates did not vary by analytic method. Biopsy and cytology specimens were inadequate for testing in 26% and 35% of cases compared to 5% of surgical specimens. Among the 1007 cases with mutation analysis performed, EGFR, KRAS, ALK, and ERBB2 alterations were detected in 22, 25, 8.5, and 2.4% of cases, respectively. EGFR mutations were highly associated with female sex, Asian race, and never smoking status; and less strongly associated with stage IV disease, presence of bone metastases, and absence of adrenal metastases. ALK rearrangements were strongly associated with never smoking status, and more weakly associated with presence of liver metastases. ERBB2 mutations were strongly associated with Asian race and never smoking status. Two mutations were seen in 2.7% of samples, all but one of which involved one or more of PIK3CA, ALK or MET.
Conclusion
Multi-institutional molecular analysis across multiple platforms, sample types, and institutions can yield consistent results and novel clinicopathological observations
Science from an Ultra-Deep, High-Resolution Millimeter-Wave Survey
Opening up a new window of millimeter-wave observations that span frequency
bands in the range of 30 to 500 GHz, survey half the sky, and are both an order
of magnitude deeper (about 0.5 uK-arcmin) and of higher-resolution (about 10
arcseconds) than currently funded surveys would yield an enormous gain in
understanding of both fundamental physics and astrophysics. In particular, such
a survey would allow for major advances in measuring the distribution of dark
matter and gas on small-scales, and yield needed insight on 1.) dark matter
particle properties, 2.) the evolution of gas and galaxies, 3.) new light
particle species, 4.) the epoch of inflation, and 5.) the census of bodies
orbiting in the outer Solar System.Comment: 5 pages + references; Submitted to the Astro2020 call for science
white paper
In Support of a Patient-Driven Initiative and Petition to Lower the High Price of Cancer Drugs
Comment in
Lowering the High Cost of Cancer Drugs--III. [Mayo Clin Proc. 2016]
Lowering the High Cost of Cancer Drugs--I. [Mayo Clin Proc. 2016]
Lowering the High Cost of Cancer Drugs--IV. [Mayo Clin Proc. 2016]
In Reply--Lowering the High Cost of Cancer Drugs. [Mayo Clin Proc. 2016]
US oncologists call for government regulation to curb drug price rises. [BMJ. 2015
The Science Performance of JWST as Characterized in Commissioning
This paper characterizes the actual science performance of the James Webb
Space Telescope (JWST), as determined from the six month commissioning period.
We summarize the performance of the spacecraft, telescope, science instruments,
and ground system, with an emphasis on differences from pre-launch
expectations. Commissioning has made clear that JWST is fully capable of
achieving the discoveries for which it was built. Moreover, almost across the
board, the science performance of JWST is better than expected; in most cases,
JWST will go deeper faster than expected. The telescope and instrument suite
have demonstrated the sensitivity, stability, image quality, and spectral range
that are necessary to transform our understanding of the cosmos through
observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures;
https://iopscience.iop.org/article/10.1088/1538-3873/acb29
The ABC130 barrel module prototyping programme for the ATLAS strip tracker
For the Phase-II Upgrade of the ATLAS Detector, its Inner Detector,
consisting of silicon pixel, silicon strip and transition radiation
sub-detectors, will be replaced with an all new 100 % silicon tracker, composed
of a pixel tracker at inner radii and a strip tracker at outer radii. The
future ATLAS strip tracker will include 11,000 silicon sensor modules in the
central region (barrel) and 7,000 modules in the forward region (end-caps),
which are foreseen to be constructed over a period of 3.5 years. The
construction of each module consists of a series of assembly and quality
control steps, which were engineered to be identical for all production sites.
In order to develop the tooling and procedures for assembly and testing of
these modules, two series of major prototyping programs were conducted: an
early program using readout chips designed using a 250 nm fabrication process
(ABCN-25) and a subsequent program using a follow-up chip set made using 130 nm
processing (ABC130 and HCC130 chips). This second generation of readout chips
was used for an extensive prototyping program that produced around 100
barrel-type modules and contributed significantly to the development of the
final module layout. This paper gives an overview of the components used in
ABC130 barrel modules, their assembly procedure and findings resulting from
their tests.Comment: 82 pages, 66 figure
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