Cancer genome-sequencing studies have revealed a remarkably high prevalence of mutations in genes encoding subunits of the SWI/SNF chromatin-remodelling complexes, with nearly 25% of all cancers ...harbouring aberrations in one or more of these genes. A role for such aberrations in tumorigenesis is evidenced by cancer predisposition in both carriers of germline loss-of-function mutations and genetically engineered mouse models with inactivation of any of several SWI/SNF subunits. Whereas many of the most frequently mutated oncogenes and tumour-suppressor genes have been studied for several decades, the cancer-promoting role of mutations in SWI/SNF genes has been recognized only more recently, and thus comparatively less is known about these alterations. Consequently, increasing research interest is being focused on understanding the prognostic and, in particular, the potential therapeutic implications of mutations in genes encoding SWI/SNF subunits. Herein, we review the burgeoning data on the mechanisms by which mutations affecting SWI/SNF complexes promote cancer and describe promising emerging opportunities for targeted therapy, including immunotherapy with immune-checkpoint inhibitors, presented by these mutations. We also highlight ongoing clinical trials open specifically to patients with cancers harbouring mutations in certain SWI/SNF genes.
Neutron stars are composed of the densest form of matter known to exist in our Universe, the composition and properties of which are still theoretically uncertain. Measurements of the masses or radii ...of these objects can strongly constrain the neutron star matter equation of state and rule out theoretical models of their composition. The observed range of neutron star masses, however, has hitherto been too narrow to rule out many predictions of 'exotic' non-nucleonic components. The Shapiro delay is a general-relativistic increase in light travel time through the curved space-time near a massive body. For highly inclined (nearly edge-on) binary millisecond radio pulsar systems, this effect allows us to infer the masses of both the neutron star and its binary companion to high precision. Here we present radio timing observations of the binary millisecond pulsar J1614-2230 that show a strong Shapiro delay signature. We calculate the pulsar mass to be (1.97 ± 0.04)M , which rules out almost all currently proposed hyperon or boson condensate equations of state (M , solar mass). Quark matter can support a star this massive only if the quarks are strongly interacting and are therefore not 'free' quarks.
Please cite this paper as: Hawkins T, Roberts J, Mangos G, Davis G, Roberts L, Brown M. Plasma uric acid remains a marker of poor outcome in hypertensive pregnancy: a retrospective cohort study. BJOG ...2012 2012;119:484–492.
Objective To examine the relationship between hyperuricaemia, haemoconcentration and maternal and fetal outcomes in hypertensive pregnancies.
Design Retrospective analysis of a database of hypertensive pregnancies.
Setting St George Hospital, a major obstetric unit in Australia.
Population A cohort of 1880 pregnant women without underlying hypertension or renal disease, referred for management of pre‐eclampsia or gestational hypertension.
Methods Demographic, clinical and biochemical data at time of referral and delivery were collected for each pregnancy. Women were grouped according to diagnosis (pre‐eclampsia or gestational hypertension) and logistic regression analysis was used to determine the relationship between uric acid, haemoglobin, haematocrit and adverse outcomes; an α level of P < 0.01 was used for statistical significance.
Main outcome measures Composites of adverse maternal and fetal outcomes.
Results In women with ‘benign’ GH (without proteinuria or any other maternal clinical feature of pre‐eclampsia) gestation‐corrected hyperuricaemia was associated with increased risk of a small‐for‐gestational‐age infant (OR 2.5; 95% CI 1.3–4.8) and prematurity (OR 3.2; 95% CI 1.4–7.2), but not with adverse maternal outcome. In the whole cohort of hypertensive pregnant women (those with pre‐eclampsia or gestational hypertension) the risk of adverse maternal outcome (OR 2.0; 95% CI 1.6–2.4) and adverse fetal outcome (OR 1.8; 95% CI 1.5–2.1) increased with increasing concentration of uric acid. Hyperuricaemia corrected for gestation provided additional strength to these associations. Haemoglobin and haematocrit were not associated with adverse pregnancy outcome.
Conclusions Hyperuricaemia in hypertensive pregnancy remains an important finding because it identifies women at increased risk of adverse maternal and particularly fetal outcome; the latter, even in women with gestational hypertension without any other feature of pre‐eclampsia.
AbstractPre-eclampsia is a common disorder that particularly affects first pregnancies. The clinical presentation is highly variable but hypertension and proteinuria are usually seen. These systemic ...signs arise from soluble factors released from the placenta as a result of a response to stress of syncytiotrophoblast. There are two sub-types: early and late onset pre-eclampsia, with others almost certainly yet to be identified. Early onset pre-eclampsia arises owing to defective placentation, whilst late onset pre-eclampsia may center around interactions between normal senescence of the placenta and a maternal genetic predisposition to cardiovascular and metabolic disease. The causes, placental and maternal, vary among individuals. Recent research has focused on placental-uterine interactions in early pregnancy. The aim now is to translate these findings into new ways to predict, prevent, and treat pre-eclampsia.
Volatile and intermediate-volatility non-methane organic gases (NMOGs) released from biomass burning were measured during
laboratory-simulated wildfires by proton-transfer-reaction time-of-flight ...mass spectrometry (PTR-ToF). We identified NMOG
contributors to more than 150 PTR ion masses using gas chromatography (GC) pre-separation with electron ionization,
H3O+ chemical ionization, and NO+ chemical ionization, an extensive literature review, and
time series correlation, providing higher certainty for ion identifications than has been previously available. Our
interpretation of the PTR-ToF mass spectrum accounts for nearly 90 % of NMOG mass detected by PTR-ToF across all fuel
types. The relative contributions of different NMOGs to individual exact ion masses are mostly similar across many fires
and fuel types. The PTR-ToF measurements are compared to corresponding measurements from open-path Fourier transform
infrared spectroscopy (OP-FTIR), broadband cavity-enhanced spectroscopy (ACES), and iodide ion chemical ionization mass
spectrometry (I− CIMS) where possible. The majority of comparisons have slopes near 1 and values of the linear
correlation coefficient, R2, of > 0.8, including compounds that are not frequently reported by PTR-MS such as
ammonia, hydrogen cyanide (HCN), nitrous acid (HONO), and propene. The exceptions include methylglyoxal and compounds that
are known to be difficult to measure with one or more of the deployed instruments. The fire-integrated emission ratios to
CO and emission factors of NMOGs from 18 fuel types are provided. Finally, we provide an overview of the chemical
characteristics of detected species. Non-aromatic oxygenated compounds are the most abundant. Furans and aromatics, while
less abundant, comprise a large portion of the OH reactivity. The OH reactivity, its major contributors, and the
volatility distribution of emissions can change considerably over the course of a fire.
To investigate whether sleep disturbances are bidirectionally related to anxiety and depression, and thus identify potential risk factors for each problem.
A systematic review was conducted on 9 ...studies (8 longitudinal, 1 retrospective) that assessed bidirectionality between a sleep disturbance, and anxiety or depression. Treatment studies were excluded, along with those solely based on clinical samples or cohorts at high risk of suffering from a sleep disturbance, anxiety and depression. Eligible studies were identified by searching PubMed, PsychINFO, Embase, and Scopus databases, and reference lists of eligible studies. Publication dates ranged from the beginning of each database to December 2011.
Syntheses of longitudinal studies suggested insomnia and sleep quality were bidirectionally related to anxiety and depression, and depression/anxiety, respectively. Childhood sleep problems significantly predicted higher levels of depression and a combined depression/anxiety variable, but not vice-versa. A one-way relationship was found where anxiety predicted excessive daytime sleepiness, but excessive daytime sleepiness was not associated with depression.
Definitive conclusions regarding bidirectionality cannot be made for most sleep disturbances due to the small number and heterogeneity of cohort samples used across studies. Nevertheless, best available evidence suggests insomnia is bidirectionally related to anxiety and depression. Clinical and theoretical implications are discussed.
Alvaro PK; Roberts RM; Harris JK. A systematic review assessing bidirectionality between sleep disturbances, anxiety, and depression.
2013;36(7):1059-1068.
Regional climate projections are used in a wide range of impact studies, from assessing future flood risk to climate change impacts on food and energy production. These model projections are ...typically at 12–50-km resolution, providing valuable regional detail but with inherent limitations, in part because of the need to parameterize convection. The first climate change experiments at convection-permitting resolution (kilometer-scale grid spacing) are now available for the United Kingdom; the Alps; Germany; Sydney, Australia; and the western United States. These models give a more realistic representation of convection and are better able to simulate hourly precipitation characteristics that are poorly represented in coarser-resolution climate models. Here we examine these new experiments to determine whether future midlatitude precipitation projections are robust from coarse to higher resolutions, with implications also for the tropics. We find that the explicit representation of the convective storms themselves, only possible in convection-permitting models, is necessary for capturing changes in the intensity and duration of summertime rain on daily and shorter time scales. Other aspects of rainfall change, including changes in seasonal mean precipitation and event occurrence, appear robust across resolutions, and therefore coarse-resolution regional climate models are likely to provide reliable future projections, provided that large-scale changes from the global climate model are reliable. The improved representation of convective storms also has implications for projections of wind, hail, fog, and lightning. We identify a number of impact areas, especially flooding, but also transport and wind energy, for which very high-resolution models may be needed for reliable future assessments.
Preeclampsia evolves in 2 stages: a placental problem that generates signals to the mother to cause a range of responses that comprise the second stage (preeclampsia syndrome). The first stage of ...early-onset preeclampsia is poor placentation, which we here call malplacentation. The spiral arteries are incompletely remodeled, leading to later placental malperfusion, relatively early in the second half of pregnancy. The long duration of the first stage (several months) is unsurprisingly associated with fetal growth restriction.
The first stage of late-onset preeclampsia, approximately 80% of total cases, is shorter (several weeks) and part of a process that is common to all pregnancies. Placental function declines as it outgrows uterine capacity, with increasing chorionic villous packing, compression of the intervillous space, and fetal hypoxia, and causes late-onset clinical presentations such as “unexplained” stillbirths, late-onset fetal growth restriction, or preeclampsia.
The second stages of early- and late-onset preeclampsia share syncytiotrophoblast stress as the most relevant feature that causes the maternal syndrome. Syncytiotrophoblast stress signals in the maternal circulation are probably the most specific biomarkers for preeclampsia. In addition, soluble fms-like tyrosine kinase-1 (mainly produced by syncytiotrophoblast) is the best-known biomarker and is routinely used in clinical practice in many locations.
How the stress signals change over time in normal pregnancies indicates that syncytiotrophoblast stress begins on average at 30 to 32 weeks’ gestation and progresses to term. At term, syncytiotrophoblast shows increasing markers of stress, including apoptosis, pyroptosis, autophagy, syncytial knots, and necrosis. We label this phenotype the “twilight placenta” and argue that it accounts for the clinical problems of postmature pregnancies.
Senescence as a stress response differs in multinuclear syncytiotrophoblast from that of mononuclear cells. Syncytiotrophoblast irreversibly acquires part of the senescence phenotype (cell cycle arrest) when it is formed by cell fusion.
The 2 pathways converge on the common pathologic endpoint, syncytiotrophoblast stress, and contribute to preeclampsia subtypes. We highlight that the well-known heterogeneity of the preeclampsia syndrome arises from different pathways to this common endpoint, influenced by maternal genetics, epigenetics, lifestyle, and environmental factors with different fetal and maternal responses to the ensuing insults. This complexity mandates a reassessment of our approach to predicting and preventing preeclampsia, and we summarize research priorities to maximize what we can learn about these important issues.
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