The current usual interstitial pneumonitis (UIP)/idiopathic pulmonary fibrosis CT scan classification system excludes probable UIP as a diagnostic category. We sought to determine the predictive ...effect of probable UIP on CT scan on histology and the effect of the promoter polymorphism in MUC5B (rs35705950) on histologic and CT scan UIP diagnosis. METHODS The cohort included 201 subjects with pulmonary fibrosis who had lung tissue samples obtained within 1 year of chest CT scan. UIP diagnosis on CT scan was categorized as inconsistent with, indeterminate, probable, or definite UIP by two to three pulmonary radiologists. Tissue slides were scored by two expert pulmonary pathologists. All subjects with available DNA (N = 200) were genotyped for rs35705950. RESULTS The proportion of CT scan diagnoses were as follows: inconsistent with (69 of 201, 34.3%), indeterminate (72 of 201, 35.8%), probable (34 of 201, 16.9%), and definite (26 of 201, 12.9%) UIP. Subjects with probable UIP on CT scan were more likely to have histologic probable/definite UIP than subjects with indeterminate UIP on CT scan (82.4% 28 of 34 vs 54.2% 39 of 72; P = .01). CT scan and microscopic honeycombing were not associated with each other ( P = .76). The minor (T) allele of the MUC5B polymorphism was associated with concordant CT scan and histologic UIP diagnosis ( P = .03). CONCLUSIONS Probable UIP on CT scan is associated with a higher rate of histologic UIP than indeterminate UIP on CT scan suggesting that they are distinct groups and should not be combined into a single CT scan category as currently recommended by guidelines. CT scan and microscopic honeycombing may be dissimilar entities. The T allele at rs35705950 predicts a UIP diagnosis by both chest CT scan and histology.
Idiopathic pulmonary fibrosis (IPF) is an untreatable lung disease with a median survival of only 3-5 years that is diagnosed using a combination of clinical, radiographic and pathologic criteria. ...Histologically, IPF is characterised by usual interstitial pneumonia (UIP), a fibrosing interstitial pneumonia with a pattern of heterogeneous, subpleural regions of fibrotic and remodelled lung. We hypothesised that gene expression profiles of lung tissue may identify molecular subtypes of disease that could classify subtypes of IPF/UIP that have clinical implications.
We collected transcriptional profiles on lung tissue from 119 patients with IPF/UIP and 50 non-diseased controls. Differential expression of individual transcripts was identified using an analysis of covariance (ANCOVA) model incorporating the clinical diagnosis of each patient as well as age, gender and smoking status. Validation was performed in an independent cohort of 111 IPF/UIP and 39 non-diseased controls. Our analysis identified two subtypes of IPF/UIP based on a strong molecular signature associated with expression of genes previously associated with fibrosis (matrix metalloproteinases, osteopontin, keratins), cilium genes and genes with unknown function. We demonstrate that elevated expression of cilium genes is associated with more extensive microscopic honeycombing and higher expression of both the airway mucin gene MUC5B and the metalloproteinase MMP7, a gene recently implicated in attenuating ciliated cell differentiation during wound repair.
Expression of cilium genes appears to identify two unique molecular phenotypes of IPF/UIP. The different molecular profiles may be relevant to therapeutic responsiveness in patients with IPF/UIP.
Background To determine the effect of the MUC5B promoter polymorphism (rs35705950) on the CT imaging appearance of pulmonary fibrosis. Methods High-resolution CT scans of 1,764 subjects were scored ...as part of a, genomewide association study with institutional review board approval; 1,491 of these had pulmonary fibrosis on CT scans and were included in the study. Two thoracic radiologists independently scored CT scans systematically. Discrepancies were resolved by a third thoracic radiologist. All patients were genotyped specifically for the rs35705950 single-nucleotide polymorphism (SNP). Two-tailed Fisher exact or χ2 tests and Student t tests or Mann-Whitney U tests were used to compare proportions and means, respectively. Results The major and minor alleles at the rs35705950 SNP are guanine (G) and thymine (T), respectively: 514 were homozygous for the major allele (G group), and 977 were heterozygous or homozygous for the minor allele (T group). The G group had a higher proportion than the T group with ground-glass opacity (62.1% vs 54.2%; P = .04). There was no significant difference between the G and T groups regarding presence of honeycombing. The T group showed a significantly higher subpleural axial distribution of fibrosis than did the G group (62.3% vs 42.2%; P < .0001). The T group showed a lower proportion of diagnoses inconsistent with usual interstitial pneumonitis (UIP; 20.3% compared with 30.5% for the G group) and a greater proportion of confident (probable UIP and UIP) UIP diagnoses (43.8% compared with 32.6% for the G group). Conclusions The MUC5B promoter polymorphism identifies a pattern of fibrosis that is different from other causes of fibrosis and may respond differently to potential therapies.
Up to 20% of cases of idiopathic interstitial pneumonia cluster in families, comprising the syndrome of familial interstitial pneumonia (FIP); however, the genetic basis of FIP remains uncertain in ...most families.
To determine if new disease-causing rare genetic variants could be identified using whole-exome sequencing of affected members from FIP families, providing additional insights into disease pathogenesis.
Affected subjects from 25 kindreds were selected from an ongoing FIP registry for whole-exome sequencing from genomic DNA. Candidate rare variants were confirmed by Sanger sequencing, and cosegregation analysis was performed in families, followed by additional sequencing of affected individuals from another 163 kindreds.
We identified a potentially damaging rare variant in the gene encoding for regulator of telomere elongation helicase 1 (RTEL1) that segregated with disease and was associated with very short telomeres in peripheral blood mononuclear cells in 1 of 25 families in our original whole-exome sequencing cohort. Evaluation of affected individuals in 163 additional kindreds revealed another eight families (4.7%) with heterozygous rare variants in RTEL1 that segregated with clinical FIP. Probands and unaffected carriers of these rare variants had short telomeres (<10% for age) in peripheral blood mononuclear cells and increased T-circle formation, suggesting impaired RTEL1 function.
Rare loss-of-function variants in RTEL1 represent a newly defined genetic predisposition for FIP, supporting the importance of telomere-related pathways in pulmonary fibrosis.
Abstract Background: Pancreatic cancer is a leading cause of cancer-related death globally. Risk factors for pancreatic cancer include common genetic variants and potentially heavy alcohol ...consumption. We assessed if genetic variants modify the association between heavy alcohol consumption and pancreatic cancer risk. Methods: We conducted a genome-wide interaction analysis of single-nucleotide polymorphisms (SNP) by heavy alcohol consumption (more than three drinks per day) for pancreatic cancer in European ancestry populations from genome-wide association studies. Our analysis included 3,707 cases and 4,167 controls from case–control studies and 1,098 cases and 1,162 controls from cohort studies. Fixed-effect meta-analyses were conducted. Results: A potential novel region of association on 10p11.22, lead SNP rs7898449 (interaction P value (Pinteraction) = 5.1 × 10−8 in the meta-analysis; Pinteraction = 2.1 × 10−9 in the case–control studies; Pinteraction = 0.91 in the cohort studies), was identified. An SNP correlated with this lead SNP is an expression quantitative trait locus for the neuropilin 1 gene. Of the 17 genomic regions with genome-wide significant evidence of association with pancreatic cancer in prior studies, we observed suggestive evidence that heavy alcohol consumption modified the association for one SNP near LINC00673, rs11655237 on 17q25.1 (Pinteraction = 0.004). Conclusions: We identified a novel genomic region that may be associated with pancreatic cancer risk in conjunction with heavy alcohol consumption located near an expression quantitative trait locus for neuropilin 1, a protein that plays an important role in the development and progression of pancreatic cancer. Impact: This work can provide insights into the etiology of pancreatic cancer, particularly in heavy drinkers.
ABSTRACT
We present the measurement of the Hubble constant, H0, with three strong gravitational lens systems. We describe a blind analysis of both PG 1115+080 and HE 0435−1223 as well as an extension ...of our previous analysis of RXJ 1131−1231. For each lens, we combine new adaptive optics (AO) imaging from the Keck Telescope, obtained as part of the SHARP (Strong-lensing High Angular Resolution Programme) AO effort, with Hubble Space Telescope (HST) imaging, velocity dispersion measurements, and a description of the line-of-sight mass distribution to build an accurate and precise lens mass model. This mass model is then combined with the COSMOGRAIL-measured time delays in these systems to determine H0. We do both an AO-only and an AO + HST analysis of the systems and find that AO and HST results are consistent. After unblinding, the AO-only analysis gives $H_{0}=82.8^{+9.4}_{-8.3}~\rm km\, s^{-1}\, Mpc^{-1}$ for PG 1115+080, $H_{0}=70.1^{+5.3}_{-4.5}~\rm km\, s^{-1}\, Mpc^{-1}$ for HE 0435−1223, and $H_{0}=77.0^{+4.0}_{-4.6}~\rm km\, s^{-1}\, Mpc^{-1}$ for RXJ 1131−1231. The joint AO-only result for the three lenses is $H_{0}=75.6^{+3.2}_{-3.3}~\rm km\, s^{-1}\, Mpc^{-1}$. The joint result of the AO + HST analysis for the three lenses is $H_{0}=76.8^{+2.6}_{-2.6}~\rm km\, s^{-1}\, Mpc^{-1}$. All of these results assume a flat Λ cold dark matter cosmology with a uniform prior on Ωm in 0.05, 0.5 and H0 in 0, 150 $\rm km\, s^{-1}\, Mpc^{-1}$. This work is a collaboration of the SHARP and H0LiCOW teams, and shows that AO data can be used as the high-resolution imaging component in lens-based measurements of H0. The full time-delay cosmography results from a total of six strongly lensed systems are presented in a companion paper.
Accurate and precise measurements of the Hubble constant are critical for testing our current standard cosmological model and revealing possibly new physics. With Hubble Space Telescope (HST) ...imaging, each strong gravitational lens system with measured time delays can allow one to determine the Hubble constant with an uncertainty of ∼7 per cent. Since HST will not last forever, we explore adaptive-optics (AO) imaging as an alternative that can provide higher angular resolution than HST imaging but has a less stable point spread function (PSF) due to atmospheric distortion. To make AO imaging useful for time-delay-lens cosmography, we develop a method to extract the unknown PSF directly from the imaging of strongly lensed quasars. In a blind test with two mock data sets created with different PSFs, we are able to recover the important cosmological parameters (time-delay distance, external shear, lens-mass profile slope, and total Einstein radius). Our analysis of the Keck AO image of the strong lens system RXJ 1131−1231 shows that the important parameters for cosmography agree with those based on HST imaging and modelling within 1σ uncertainties. Most importantly, the constraint on the model time-delay distance by using AO imaging with 0.09 arcsec resolution is tighter by ∼50 per cent than the constraint of time-delay distance by using HST imaging with 0.09 arcsec when a power-law mass distribution for the lens system is adopted. Our PSF reconstruction technique is generic and applicable to data sets that have multiple nearby point sources, enabling scientific studies that require high-precision models of the PSF.
In a randomized trial involving patients with limb ischemia, the incidence of a major adverse limb event or death at 2.7 years was lower in the surgical group than in the endovascular group.
Time-delay strong lensing provides a unique way to directly measure the Hubble constant (H0). The precision of the H0measurement depends on the uncertainties in the time-delay measurements, the mass ...distribution of the main deflector(s), and the mass distribution along the line of sight. Tie & Kochanek have proposed a new microlensing effect on time delays based on differential magnification of the coherent accretion disc variability of the lensed quasar. If real, this effect could significantly broaden the uncertainty on the time-delay measurements by up to 30 per cent for lens systems such as PG 1115+080, which have relatively short time delays and monitoring over several different epochs. In this paper we develop a new technique that uses the cosmological time-delay ratios and simulated microlensing maps within a Bayesian framework in order to limit the allowed combinations of microlensing delays and thus to lessen the uncertainties due to the proposed effect. We show that, under the assumption of Tie & Kochanek, the uncertainty on the time-delay distance (D∆t, which is proportional to 1/H0) of the short time-delay (18 d) lens, PG 1115+080, increases from 7 per cent to ̃10 per cent by simultaneously fitting the three time-delay measurements from the three different data sets across 20 yr, while in the case of the long time-delay (̃90 d) lens, the microlensing effect on time delays is negligible as the uncertainty on DSUB∆t/SUB of RXJ 1131-1231 only increases from ̃2.5 per cent to 2.6 per cent.
ABSTRACT
Strongly lensed quasars can provide measurements of the Hubble constant (H0) independent of any other methods. One of the key ingredients is exquisite high-resolution imaging data, such as ...Hubble Space Telescope (HST) imaging and adaptive-optics (AO) imaging from ground-based telescopes, which provide strong constraints on the mass distribution of the lensing galaxy. In this work, we expand on the previous analysis of three time-delay lenses with AO imaging (RX J1131−1231, HE 0435−1223, and PG 1115+080), and perform a joint analysis of J0924+0219 by using AO imaging from the Keck telescope, obtained as part of the Strong lensing at High Angular Resolution Program (SHARP) AO effort, with HST imaging to constrain the mass distribution of the lensing galaxy. Under the assumption of a flat Λ cold dark matter (ΛCDM) model with fixed Ωm = 0.3, we show that by marginalizing over two different kinds of mass models (power-law and composite models) and their transformed mass profiles via a mass-sheet transformation, we obtain $\Delta t_{\rm BA}=6.89\substack{+0.8\\-0.7}\, h^{-1}\hat{\sigma }_{v}^{2}$ d, $\Delta t_{\rm CA}=10.7\substack{+1.6\\-1.2}\, h^{-1}\hat{\sigma }_{v}^{2}$ d, and $\Delta t_{\rm DA}=7.70\substack{+1.0\\-0.9}\, h^{-1}\hat{\sigma }_{v}^{2}$ d, where $h=H_{0}/100\,\rm km\, s^{-1}\, Mpc^{-1}$ is the dimensionless Hubble constant and $\hat{\sigma }_{v}=\sigma ^{\rm ob}_{v}/(280\,\rm km\, s^{-1})$ is the scaled dimensionless velocity dispersion. Future measurements of time delays with 10 per cent uncertainty and velocity dispersion with 5 per cent uncertainty would yield a H0 constraint of ∼15 per cent precision.
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