Objectives The aim of this study was to determine whether ectopic fat depots are prospectively associated with cardiovascular disease, cancer, and all-cause mortality. Background The morbidity ...associated with excess body weight varies among individuals of similar body mass index. Ectopic fat depots may underlie this risk differential. However, prospective studies of directly measured fat are limited. Methods Participants from the Framingham Heart Study (n = 3,086; 49% women; mean age of 50.2 years) underwent assessment of fat depots (visceral adipose tissue, pericardial adipose tissue, and periaortic adipose tissue) using multidetector computed tomography and were followed up longitudinally for a median of 5.0 years. Cox proportional hazards regression models were used to examine the association of each fat depot (per 1 SD increment) with the risk of incident cardiovascular disease, cancer, and all-cause mortality after adjustment for standard risk factors, including body mass index. Results Overall, there were 90 cardiovascular events, 141 cancer events, and 71 deaths. After multivariable adjustment, visceral adipose tissue was associated with cardiovascular disease (hazard ratio: 1.44; 95% confidence interval: 1.08 to 1.92; p = 0.01) and cancer (hazard ratio: 1.43; 95% confidence interval: 1.12 to 1.84; p = 0.005). Addition of visceral adipose tissue to a multivariable model that included body mass index modestly improved cardiovascular risk prediction (net reclassification improvement of 16.3%). None of the fat depots were associated with all-cause mortality. Conclusions Visceral adiposity is associated with incident cardiovascular disease and cancer after adjustment for clinical risk factors and generalized adiposity. These findings support the growing appreciation of a pathogenic role of ectopic fat.
Declines in insect pollinators across Europe have raised concerns about the supply of pollination services to agriculture. Simultaneously, EU agricultural and biofuel policies have encouraged ...substantial growth in the cultivated area of insect pollinated crops across the continent. Using data from 41 European countries, this study demonstrates that the recommended number of honeybees required to provide crop pollination across Europe has risen 4.9 times as fast as honeybee stocks between 2005 and 2010. Consequently, honeybee stocks were insufficient to supply >90% of demands in 22 countries studied. These findings raise concerns about the capacity of many countries to cope with major losses of wild pollinators and highlight numerous critical gaps in current understanding of pollination service supplies and demands, pointing to a pressing need for further research into this issue.
NRF2 Activation in Cancer: From DNA to Protein Cloer, Erica W; Goldfarb, Dennis; Schrank, Travis P ...
Cancer research (Chicago, Ill.),
03/2019, Letnik:
79, Številka:
5
Journal Article
Recenzirano
Odprti dostop
The Cancer Genome Atlas catalogued alterations in the Kelch-like ECH-associated protein 1 and nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway in 6.3% of patient samples across ...226 studies, with significant enrichment in lung and upper airway cancers. These alterations constitutively activate NRF2-dependent gene transcription to promote many of the cancer hallmarks, including cellular resistance to oxidative stress, xenobiotic efflux, proliferation, and metabolic reprogramming. Almost universally, NRF2 activity strongly associates with poor patient prognosis and chemo- and radioresistance. Yet to date, FDA-approved drugs targeting NRF2 activity in cancer have not been realized. Here, we review various mechanisms that contribute to NRF2 activation in cancer, organized around the central dogma of molecular biology (i) at the DNA level with genomic and epigenetic alterations, (ii) at the RNA level including differential mRNA splicing and stability, and (iii) at the protein level comprising altered posttranslational modifications and protein-protein interactions. Ultimately, defining and understanding the mechanisms responsible for NRF2 activation in cancer may lead to novel targets for therapeutic intervention.
Summary
Background
Tumour necrosis factor (TNF)‐antagonists have an established role in the treatment of inflammatory bowel diseases (IBDs), however, subtherapeutic drug levels and the formation of ...anti‐drug antibodies (ADAs) may decrease their efficacy.
Aim
The evidence supporting the use of therapeutic drug monitoring (TDM) based clinical algorithms for infliximab (IFX) and their role in clinical practice will be discussed.
Methods
The literature was reviewed to identify relevant articles on the measurement of IFX levels and antibodies‐to‐infliximab.
Results
Treatment algorithms for IBD have evolved from episodic monotherapy used in patients refractory to all other treatments, to long‐term combination therapy initiated early in the disease course. Improved remission rates have been observed with this paradigm shift, nevertheless many patients ultimately lose response to therapy. Although empiric dose optimization or switching agents constitute the current standard of care for secondary failure, these interventions have not been applied in an evidence‐based manner and are probably not cost‐effective. Multiple TDM‐based algorithms have been developed to identify patients that may benefit from measurement of IFX and ADA levels to guide adjustments to therapy.
Conclusions
Therapeutic drug monitoring offers a rational approach to the management of secondary failure to IFX. This concept has gained momentum based on evidence from case series, cohort studies and post‐hoc analyses of randomised controlled trials.
In a series of essays, conferences, and lectures over the period 1959–73, Michel Foucault directly engaged the writings of Nietzsche. This article demonstrates the five different modalities of ...Foucault's use of Nietzsche’s writings: namely, critical, epistemological, linguistic, alethurgic, and political. Each of these modalities is tied to a particular intellectual turning point in Foucault’s philosophical investigations and can be located chronologically in five important texts from that period.
In recent years, there has been remarkable change in societal acceptance of lesbians and gay men. This meta-analysis explored whether this positive shift has reduced the gender difference in these ...attitudes. We tested Kite and Whitley’s (
1996
) gender belief system model and replicated their finding that heterosexual men held more negative attitudes toward gay people (
g
. = 0.37,
k
= 245,
N
= 98,295), gay behavior (
g.
= 0.22,
k
= 68,
N
= 98,734), and gay civil rights (
g.
= 0.16,
k
= 80,
N
= 89,187). We also found that heterosexual men were more likely to report engaging in anti-gay behavior (
g.
= 0.53,
k
= 7,
N
= 2,509), endorsing gay stereotypes (
g.
= 0.17,
k
= 17,
N
= 6,936), and wanting to avoid contact with gay men (
g.
= 0.49,
k
= 7,
N
= 2,178). However, heterosexual women reported a stronger desire to avoid contact with lesbians than did heterosexual men (
g.
= -0.36,
k
= 5,
N
= 1,339). For the most part, gender differences remained stable over time; the exceptions were attitudes toward same-gender sexual behavior and attitudes toward lesbian and gay civil rights, which showed small increases. Gender differences in anti-gay prejudice were mediated by gender differences in traditional gender-role beliefs. Moderator variables included participant group, type of measure, and target group.
Most bees display an array of strategies for building their nests, and the availability of nesting resources plays a significant role in organizing bee communities. Although urbanization can cause ...local species extinction, many bee species persist in urbanized areas. We studied the response of a bee community to winter-installed human-made nesting structures (bee hotels and soil squares, i.e. 0.5 m deep holes filled with soil) in urbanized sites. We investigated the colonization pattern of these structures over two consecutive years to evaluate the effect of age and the type of substrates (e.g. logs, stems) provided on colonization. Overall, we collected 54 species. In the hotels, two gregarious species,
Osmia bicornis
L. and
O. cornuta
Latr. dominated the community (over 87 % of the data). Over 2 years, the age of the soil squares did not affect their level of colonization and the same was true for the hotels with respect to
O. bicornis
and ‘other species’. However,
O. cornuta
occurred less often and raised fewer descendants in 1-year old hotels than in new ones. Bee nesting was not affected by the soil texture and, among above-ground nesting bees, only
O. bicornis
showed a preference for some substrates, namely
Acer
sp. and
Catalpa
sp. In a context of increasing urbanization and declining bee populations, much attention has focused upon improving the floral resources available for bees, while little effort has been paid to nesting resources. Our results indicate that, in addition to floral availability, nesting resources should be taken into account in the development of urban green areas to promote a diverse bee community.
Summary
Neutrophils are detected in inflamed colon in Crohn’s disease (CD). However, whether the frequency and/or activation of circulating or gut tissue neutrophils correlate with endoscopic ...severity remains to be investigated. A cohort of 73 CD patients was prospectively enrolled according to endoscopic severity and treatment history. Individuals with active disease were stratified using the Montreal classification. Harvey–Bradshaw Index (HBI) and Simple Endoscopic Score for Crohn’s Disease (SES‐CD) were performed at the time of ileocolonoscopy. Frequency of neutrophils and their expression of CD66b and CD64 were assessed in paired blood and colonic biopsies using flow cytometry. The percentage of neutrophils increased in inflamed colon and correlated with SES‐CD in the entire cohort of patients examined, as well as in the subgroup with inflammatory (B1) active disease. SES‐CD further correlated with neutrophil CD66b expression in mucosa but not blood and, conversely, with neutrophil CD64 expression in blood but not mucosa. However, the evaluation of neutrophil activation in mucosa when compared to blood reflected disease activity more clearly. Finally, a neutrophil activation power index (CD66b in mucosa X CD64 in blood) that correlated with SES‐CD discriminated between patients with mild and severe disease. In conclusion, the frequency and activation of colonic neutrophils correlated with SES‐CD, highlighting that mucosal neutrophils are associated with disease severity in CD.
In this prospective single‐cell analysis study, neutrophils up‐regulated CD66b expression in inflamed CD mucosa while CD64 expression was augmented on circulating neutrophils in CD patients with endoscopic active disease relative to control groups. Neutrophil CD66b expression in mucosa and, conversely, neutrophil CD64 expression in blood correlated with SES‐CD in CD patients. We thus propose that recruitment of activated neutrophils in inflamed mucosa is associated with disease severity in Crohn’s disease.
Bee pollinators are currently recorded with many different sampling methods. However, the relative performances of these methods have not been systematically evaluated and compared. In response to ...the strong need to record ongoing shifts in pollinator diversity and abundance, global and regional pollinator initiatives must adopt standardized sampling protocols when developing large-scale and long-term monitoring schemes. We systematically evaluated the performance of six sampling methods (observation plots, pan traps, standardized and variable transect walks, trap nests with reed internodes or paper tubes) that are commonly used across a wide range of geographical regions in Europe and in two habitat types (agricultural and seminatural). We focused on bees since they represent the most important pollinator group worldwide. Several characteristics of the methods were considered in order to evaluate their performance in assessing bee diversity: sample coverage, observed species richness, species richness estimators, collector biases (identified by subunit-based rarefaction curves), species composition of the samples, and the indication of overall bee species richness (estimated from combined total samples). The most efficient method in all geographical regions, in both the agricultural and seminatural habitats, was the pan trap method. It had the highest sample coverage, collected the highest number of species, showed negligible collector bias, detected similar species as the transect methods, and was the best indicator of overall bee species richness. The transect methods were also relatively efficient, but they had a significant collector bias. The observation plots showed poor performance. As trap nests are restricted to cavity-nesting bee species, they had a naturally low sample coverage. However, both trap nest types detected additional species that were not recorded by any of the other methods. For large-scale and long-term monitoring schemes with surveyors with different experience levels, we recommend pan traps as the most efficient, unbiased, and cost-effective method for sampling bee diversity. Trap nests with reed internodes could be used as a complementary sampling method to maximize the numbers of collected species. Transect walks are the principal method for detailed studies focusing on plant—pollinator associations. Moreover, they can be used in monitoring schemes after training the surveyors to standardize their collection skills.
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