Malignant pleural mesothelioma (MPM) is a very aggressive tumor with no known curative treatment. Better knowledge of the molecular mechanisms of mesothelial carcinogenesis is required to develop new ...therapeutic strategies. MPM, like all cancer cells, needs to maintain telomere length to prevent senescence. Previous studies suggested that the telomere lengthening mechanism in MPM is based mainly on telomerase activity. For this reason, we focused on the key catalytic enzyme, TERT (telomerase reverse transcriptase), by analyzing its gene expression in MPM and by studying the mechanism underlying its upregulation. We used our large collection of MPM composed of 61 MPM in culture and 71 frozen MPM tumor samples. Evaluation of TERT mRNA expression by quantitative RT-PCR showed overexpression in MPM in culture compared with normal mesothelial cells, and in MPM tumor samples compared with normal pleura. We identified a 'hot spot' of mutations in the TERT gene core promoter in both MPM in culture and in MPM tumor samples with an overall frequency of 15%. Furthermore, data clearly identified mutation in the TERT promoter as a mechanism of TERT mRNA upregulation in MPM. In contrast, gene copy number amplification was not associated with TERT overexpression. Then, we analyzed the clinicopathological, etiological and genetic characteristics of MPM with mutations in the TERT promoter. TERT promoter mutations were more frequent in MPM with sarcomatoid histologic subtype (P<0.01), and they were frequently associated with CDKN2A gene inactivation (P=0.03). In conclusion, a subgroup of MPM presents TERT promoter mutations, which lead to TERT mRNA upregulation. This is the first recurrent gain-of-function oncogenic mutations identified in MPM.
Pyrocumulonimbus (pyroCb) are wildfire-generated convective clouds that can inject smoke directly into the stratosphere. PyroCb have been tracked for years, yet their apparent rarity and episodic ...nature lead to highly uncertain climate impacts. In situ measurements of pyroCb smoke reveal its distinctive and exceptionally stable aerosol properties and define the long-term influence of pyroCb activity on the stratospheric aerosol budget. Analysis of 13 years of airborne observations shows that pyroCb are responsible for 10 to 25% of the black carbon and organic aerosols in the "present-day" lower stratosphere, with similar impacts in both the North and South Hemispheres. These results suggest that, should pyroCb increase in frequency and/or magnitude in future climates, they could generate dominant trends in stratospheric aerosol.
Atmospheric marine aerosol particles impact Earth's albedo and climate. These particles can be primary or secondary and come from a variety of sources, including sea salt, dissolved organic matter, ...volatile organic compounds, and sulfur-containing compounds. Dimethylsulfide (DMS) marine emissions contribute greatly to the global biogenic sulfur budget, and its oxidation products can contribute to aerosol mass, specifically as sulfuric acid and methanesulfonic acid (MSA). Further, sulfuric acid is a known nucleating compound, and MSA may be able to participate in nucleation when bases are available. As DMS emissions, and thus MSA and sulfuric acid from DMS oxidation, may have changed since pre-industrial times and may change in a warming climate, it is important to characterize and constrain the climate impacts of both species. Currently, global models that simulate aerosol size distributions include contributions of sulfate and sulfuric acid from DMS oxidation, but to our knowledge, global models typically neglect the impact of MSA on size distributions.
Glyoxal (CHOCHO), the simplest dicarbonyl in the
troposphere, is a potential precursor for secondary organic aerosol (SOA)
and brown carbon (BrC) affecting air quality and climate. The airborne
...measurement of CHOCHO concentrations during the KORUS-AQ (KORea–US Air
Quality study) campaign in 2016 enables detailed quantification of loss
mechanisms pertaining to SOA formation in the real atmosphere. The
production of this molecule was mainly from oxidation of aromatics (59 %)
initiated by hydroxyl radical (OH). CHOCHO loss to aerosol was found to be
the most important removal path (69 %) and contributed to roughly
∼ 20 % (3.7 µg sm−3 ppmv−1 h−1,
normalized with excess CO) of SOA growth in the first 6 h in Seoul
Metropolitan Area. A reactive uptake coefficient (γ) of
∼ 0.008 best represents the loss of CHOCHO by surface uptake
during the campaign. To our knowledge, we show the first field observation
of aerosol surface-area-dependent (Asurf) CHOCHO uptake, which diverges
from the simple surface uptake assumption as Asurf increases in ambient
condition. Specifically, under the low (high) aerosol loading, the CHOCHO
effective uptake rate coefficient, keff,uptake, linearly increases
(levels off) with Asurf; thus, the irreversible surface uptake is a
reasonable (unreasonable) approximation for simulating CHOCHO loss to
aerosol. Dependence on photochemical impact and changes in the chemical and
physical aerosol properties “free water”, as well as aerosol viscosity,
are discussed as other possible factors influencing CHOCHO uptake rate. Our
inferred Henry's law coefficient of CHOCHO, 7.0×108 M atm−1, is ∼ 2 orders of magnitude higher than those
estimated from salting-in effects constrained by inorganic salts only
consistent with laboratory findings that show similar high partitioning into
water-soluble organics, which urges more understanding on CHOCHO solubility
under real atmospheric conditions.
In situ measurements of aerosol microphysical, chemical, and optical properties were made during global-scale flights from 2016-2018 as part of the Atmospheric Tomography Mission (ATom). The NASA ...DC-8 aircraft flew from â¼ 84.sup." N to â¼ 86.sup." S latitude over the Pacific, Atlantic, Arctic, and Southern oceans while profiling nearly continuously between altitudes of â¼ 160 m and â¼ 12 km. These global circuits were made once each season. Particle size distributions measured in the aircraft cabin at dry conditions and with an underwing probe at ambient conditions were combined with bulk and single-particle composition observations and measurements of water vapor, pressure, and temperature to estimate aerosol hygroscopicity and hygroscopic growth factors and calculate size distributions at ambient relative humidity. These reconstructed, composition-resolved ambient size distributions were used to estimate intensive and extensive aerosol properties, including single-scatter albedo, the asymmetry parameter, extinction, absorption, Ãngström exponents, and aerosol optical depth (AOD) at several wavelengths, as well as cloud condensation nuclei (CCN) concentrations at fixed supersaturations and lognormal fits to four modes. Dry extinction and absorption were compared with direct in situ measurements, and AOD derived from the extinction profiles was compared with remotely sensed AOD measurements from the ground-based Aerosol Robotic Network (AERONET); this comparison showed no substantial bias.
Hepatocellular carcinoma is a frequent consequence of alcohol-related liver disease, with variable incidence among heavy drinkers. We did a genome-wide association study (GWAS) to identify common ...genetic variants for alcohol-related hepatocellular carcinoma.
We conducted a two-stage case-control GWAS in a discovery cohort of 2107 unrelated European patients with alcohol-related liver disease aged 20–92 years recruited between Oct 22, 1993, and March 12, 2017. Cases were patients with alcohol-related hepatocellular carcinoma diagnosed by imaging or histology. Controls were patients with alcohol-related liver disease without hepatocellular carcinoma. We used an additive logistic regression model adjusted for the first ten principal components to assess genetic variants associated with alcohol-related hepatocellular carcinoma. We did another analysis with adjustment for age, sex, and liver fibrosis. New candidate associations (p<1 × 10−6) and variants previously associated with alcohol-related hepatocellular carcinoma were evaluated in a validation cohort of 1933 patients with alcohol-related liver disease aged 29–92 years recruited between July 21, 1995, and May 2, 2019. We did a meta-analysis of the two case–control cohorts.
The discovery cohort included 775 cases and 1332 controls. Of 7 962 325 variants assessed, we identified WNT3A-WNT9A (rs708113; p=1·11 × 10−8) and found support for previously reported regions associated with alcohol-related hepatocellular carcinoma risk at TM6SF2 (rs58542926; p=6·02 × 10−10), PNPLA3 (rs738409; p=9·29 × 10−7), and HSD17B13 (rs72613567; p=2·49 × 10−4). The validation cohort included 874 cases and 1059 controls and three variants were replicated: WNT3A-WNT9A (rs708113; p=1·17 × 10−3), TM6SF2 (rs58542926; p=4·06 × 10−5), and PNPLA3 (rs738409; p=1·17 × 10−4). All three variants reached GWAS significance in the meta-analysis: WNT3A-WNT9A (odds ratio 0·73, 95% CI 0·66–0·81; p=3·93 × 10−10), TM6SF2 (1·77, 1·52–2·07; p=3·84×10−13), PNPLA3 (1·34, 1·22–1·47; p=7·30 × 10−10). Adjustment for clinical covariates yielded similar results. We observed an additive effect of at-risk alleles on alcohol-related hepatocellular carcinoma. WNT3A-WNT9A rs708113 was not associated with liver fibrosis.
WNT3A-WNT9A is a susceptibility locus for alcohol-related hepatocellular carcinoma, suggesting an early role of the Wnt–β-catenin pathway in alcohol-related hepatocellular carcinoma carcinogenesis.
Ligue Nationale contre le Cancer, Bpifrance, INSERM, AFEF, CARPEM, Labex OncoImmunology, and Agence Nationale de la Recherche.
PDF
