Noninvasive genotyping using plasma cell-free DNA (cfDNA) has the potential to obviate the need for some invasive biopsies in cancer patients while also elucidating disease heterogeneity. We sought ...to develop an ultra-deep plasma next-generation sequencing (NGS) assay for patients with non-small-cell lung cancers (NSCLC) that could detect targetable oncogenic drivers and resistance mutations in patients where tissue biopsy failed to identify an actionable alteration.
Plasma was prospectively collected from patients with advanced, progressive NSCLC. We carried out ultra-deep NGS using cfDNA extracted from plasma and matched white blood cells using a hybrid capture panel covering 37 lung cancer-related genes sequenced to 50000× raw target coverage filtering somatic mutations attributable to clonal hematopoiesis. Clinical sensitivity and specificity for plasma detection of known oncogenic drivers were calculated and compared with tissue genotyping results. Orthogonal ddPCR validation was carried out in a subset of cases.
In 127 assessable patients, plasma NGS detected driver mutations with variant allele fractions ranging from 0.14% to 52%. Plasma ddPCR for EGFR or KRAS mutations revealed findings nearly identical to those of plasma NGS in 21 of 22 patients, with high concordance of variant allele fraction (r=0.98). Blinded to tissue genotype, plasma NGS sensitivity for de novo plasma detection of known oncogenic drivers was 75% (68/91). Specificity of plasma NGS in those who were driver-negative by tissue NGS was 100% (19/19). In 17 patients with tumor tissue deemed insufficient for genotyping, plasma NGS identified four KRAS mutations. In 23 EGFR mutant cases with acquired resistance to targeted therapy, plasma NGS detected potential resistance mechanisms, including EGFR T790M and C797S mutations and ERBB2 amplification.
Ultra-deep plasma NGS with clonal hematopoiesis filtering resulted in de novo detection of targetable oncogenic drivers and resistance mechanisms in patients with NSCLC, including when tissue biopsy was inadequate for genotyping.
Over a quarter of drugs that enter clinical development fail because they are ineffective. Growing insight into genes that influence human disease may affect how drug targets and indications are ...selected. However, there is little guidance about how much weight should be given to genetic evidence in making these key decisions. To answer this question, we investigated how well the current archive of genetic evidence predicts drug mechanisms. We found that, among well-studied indications, the proportion of drug mechanisms with direct genetic support increases significantly across the drug development pipeline, from 2.0% at the preclinical stage to 8.2% among mechanisms for approved drugs, and varies dramatically among disease areas. We estimate that selecting genetically supported targets could double the success rate in clinical development. Therefore, using the growing wealth of human genetic data to select the best targets and indications should have a measurable impact on the successful development of new drugs.
The Physics of the B Factories Bevan, Adrian; Golob, Bostjan; Mannel, Thomas ...
The European physical journal. C, Particles and fields,
March 2015, Letnik:
74, Številka:
11
eBook, Journal Article
Recenzirano
Odprti dostop
This work is on the Physics of the B Factories. Part A of this book contains a brief description of the SLAC and KEK B Factories as well as their detectors, BaBar and Belle, and data taking related ...issues. Part B discusses tools and methods used by the experiments in order to obtain results. The results themselves can be found in Part C.
Abrupt decreases of the Atlantic meridional overturning circulation (MOC) during the Late Pleistocene have been directly linked to catastrophic discharges of glacimarine freshwater, triggering ...disruption of northward marine heat transport and causing global climate changes. Here we provide measurements of excess sedimentary 231Pa/230Th from a high‐accumulation sediment drift deposit in the NE Atlantic that record a sequence of sudden variations in the rate of MOC, associated deep ocean ventilation and surface‐ocean climatology. The data series reveal a sequential decrease in the MOC rate at ∼18.0 ka BP ago that coincides with only transient and localized freshwater inputs. This change represents a substantial, though not total, cessation in MOC that predates the major Heinrich (H1) meltwater event by at least 1,200 years. These results highlight the potential of targeted freshwater perturbations in promoting substantial MOC changes without a direct linking with catastrophic freshwater surges.
A
bstract
Charged lepton flavor violation is forbidden in the Standard Model but possible in several new physics scenarios. In many of these models, the radiative decays
τ
±
→
ℓ
±
γ
(
ℓ
=
e, μ
) are ...predicted to have a sizeable probability, making them particularly interesting channels to search at various experiments. An updated search via
τ
±
→
ℓ
±
γ
using full data of the Belle experiment, corresponding to an integrated luminosity of 988 fb
−
1
, is reported for charged lepton flavor violation. No significant excess over background predictions from the Standard Model is observed, and the upper limits on the branching fractions,
B
(
τ
±
→
μ
±
γ
) ≤ 4
.
2 × 10
−
8
and
B
(
τ
±
→
e
±
γ
) ≤ 5
.
6 × 10
−
8
, are set at 90% confidence level.
A
bstract
We report a new measurement of the
e
+
e
−
→
ϒ(
nS
)
π
+
π
−
(
n
= 1
,
2
,
3) cross sections at energies from 10
.
52 to 11
.
02 GeV using data collected with the Belle detector at the KEKB ...asymmetric-energy
e
+
e
−
collider. We observe a new structure in the energy dependence of the cross sections; if described by a Breit-Wigner function its mass and width are found to be
M
=
10752.7
±
5.9
−
1.1
+
0.7
MeV
/
c
2
and
Γ
=
35.5
−
11.3
−
3.3
+
17.6
+
3.9
MeV, where the first error is statistical and the second is systematic. The global significance of the new structure including systematic uncertainty is 5.2 standard deviations. We also find evidence for the
e
+
e
−
→
ϒ (1
S
)
π
+
π
−
process at the energy 10
.
52 GeV, which is below the
B
B
¯
threshold.
The interface between transition metal compounds provides a rich playground for emergent phenomena. Recently, significantly enhanced superconductivity has been reported for single-layer FeSe on ...Nb-doped SrTiO3 substrate. Yet it remains mysterious how the interface affects the superconductivity. Here we use in situ angle-resolved photoemission spectroscopy to investigate various FeSe-based heterostructures grown by molecular beam epitaxy, and uncover that electronic correlations and superconducting gap-closing temperature (Tg) are tuned by interfacial effects. Tg up to 75 K is observed in extremely tensile-strained single-layer FeSe on Nb-doped BaTiO3, which sets a record high pairing temperature for both Fe-based superconductor and monolayer-thick films, providing a promising prospect on realizing more cost-effective superconducting device. Moreover, our results exclude the direct correlation between superconductivity and tensile strain or the energy of an interfacial phonon mode, and highlight the critical and non-trivial role of FeSe/oxide interface on the high Tg, which provides new clues for understanding its origin.
In this two‐part paper, a description is provided of a version of the AM4.0/LM4.0 atmosphere/land model that will serve as a base for a new set of climate and Earth system models (CM4 and ESM4) under ...development at NOAA's Geophysical Fluid Dynamics Laboratory (GFDL). This version, with roughly 100 km horizontal resolution and 33 levels in the vertical, contains an aerosol model that generates aerosol fields from emissions and a “light” chemistry mechanism designed to support the aerosol model but with prescribed ozone. In Part 1, the quality of the simulation in AMIP (Atmospheric Model Intercomparison Project) mode—with prescribed sea surface temperatures (SSTs) and sea‐ice distribution—is described and compared with previous GFDL models and with the CMIP5 archive of AMIP simulations. The model's Cess sensitivity (response in the top‐of‐atmosphere radiative flux to uniform warming of SSTs) and effective radiative forcing are also presented. In Part 2, the model formulation is described more fully and key sensitivities to aspects of the model formulation are discussed, along with the approach to model tuning.
Key Points
A description is provided of the AM4.0/LM4.0 model that will serve as a base for a new set of GFDL/NOAA climate and Earth system models
The simulation quality in AMIP mode is described and compared with previous GFDL models and with the CMIP5 archive of AMIP simulations
The model's Cess sensitivity and effective radiative forcing are presented
Umbilical cord blood-derived mononuclear cell (UCB-MNC) transplants improve recovery in animal spinal cord injury (SCI) models. We transplanted UCB-MNCs into 28 patients with chronic complete SCI in ...Hong Kong (HK) and Kunming (KM). Stemcyte Inc. donated UCB-MNCs isolated from human leukocyte antigen (HLA ≥4:6)-matched UCB units. In HK, four patients received four 4-μl injections (1.6 million cells) into dorsal entry zones above and below the injury site, and another four received 8-μl injections (3.2 million cells). The eight patients were an average of 13 years after C5-T10 SCI. Magnetic resonance diffusion tensor imaging of five patients showed white matter gaps at the injury site before treatment. Two patients had fiber bundles growing across the injury site by 12 months, and the rest had narrower white matter gaps. Motor, walking index of SCI (WISCI), and spinal cord independence measure (SCIM) scores did not change. In KM, five groups of four patients received four 4-μl (1.6 million cells), 8-μl (3.2 million cells), 16-μl injections (6.4 million cells), 6.4 million cells plus 30 mg/kg methylprednisolone (MP), or 6.4 million cells plus MP and a 6-week course of oral lithium carbonate (750 mg/day). KM patients averaged 7 years after C3-T11 SCI and received 3–6 months of intensive locomotor training. Before surgery, only two patients walked 10 m with assistance and did not need assistance for bladder or bowel management before surgery. The rest could not walk or do their bladder and bowel management without assistance. At about a year (41–87 weeks), WISCI and SCIM scores improved: 15/20 patients walked 10 m (p = 0.001) and 12/20 did not need assistance for bladder management (p = 0.001) or bowel management (p = 0.002). Five patients converted from complete to incomplete (two sensory, three motor; p = 0.038) SCI. We conclude that UCB-MNC transplants and locomotor training improved WISCI and SCIM scores. We propose further clinical trials.
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