Telomerase reverse transcriptase (TERT)
is the catalytic subunit of the enzyme telomerase and is essential for telomerase activity. Upregulation of
TERT
expression and resulting telomerase activity ...occurs in the large majority of malignancies, including thyroid cancer. This upregulation results in continued cellular proliferation and avoidance of cellular senescence and cell death. In this review we will briefly introduce
TERT
and telomerase activity as it pertains to thyroid cancer and, highlight the effects of
TERT
on cancer cells. We will also explore in detail the different
TERT
regulatory strategies and how
TERT
is reactivated in thyroid cancer cells, specifically. These regulatory mechanisms include both activating single base pair
TERT
promoter mutations and epigenetic changes at the promoter, including changes in CpG methylation and histone modifications that affect chromatin structure. Further, regulation includes the allele-specific regulation of the
TERT
promoter in thyroid cancer cells harboring the
TERT
promoter mutation. These entail allele-specific transcriptional activator binding, DNA methylation, histone modifications, and mono-allelic expression of
TERT
. Lastly,
TERT
copy number alterations and alternative splicing are also implicated. Both amplifications of the
TERT
locus and increased full-length transcripts and decreased inactive and dominant negative isoforms result in active telomerase. Finally, the clinical significance of
TERT
in thyroid cancer is also reviewed.
Intestinal mucus provides a significant barrier to transport of orally delivered drug carriers, as well as other particulates (e.g. food, microbes). The relative significance of particle size, ...surface chemistry, and dosing medium to mucus barrier properties is not well characterized, but important in designing delivery systems targeted to the intestinal mucosa. In this study, multiple particle tracking (MPT) was used to study diffusion of 20-500 nm diameter carboxylate- and polyethylene glycol-(PEG-)functionalized polystyrene model carriers through intestinal mucus. The impact of exposure to mucus in buffer versus a partially digested triglyceride mixture was explored. Effective diffusivity of particles in intestinal mucus decreased with an increasing particle size less than and more than theoretically (Stokes-Einstein) expected in a homogenous medium when dosed in buffer and model-fed state intestinal contents, respectively. For example, effective diffusivity decreased 2.9- versus 20-fold with increase in the particle size from 100 to 500 nm when dosed to mucus in buffer versus lipid-containing medium. Functionalization with PEG dramatically decreased sensitivity to lipids in a dosing medium. The results indicate that reduction of particle size may increase particle transport through intestinal mucus barriers, but these effects are strongly dependent on intestinal contents and particle surface chemistry.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The Pneumonia Score Index (PSI) was developed to estimate the risk of dying within 30 days of presentation for community-acquired pneumonia patients and is a strong predictor of 30-day mortality ...after COVID-19. However, three of its required 20 variables (skilled nursing home, altered mental status and pleural effusion) are not discreetly available in the electronic medical record (EMR), resulting in manual chart review for these 3 factors. The goal of this study is to compare a simplified 17-factor version (PSI-17) to the original (denoted PSI-20) in terms of prediction of 30-day mortality in COVID-19.
In this retrospective cohort study, the hospitalized patients with confirmed SARS-CoV-2 infection between 2/28/20-5/28/20 were identified to compare the predictive performance between PSI-17 and PSI-20. Correlation was assessed between PSI-17 and PSI-20, and logistic regressions were performed for 30-day mortality. The predictive abilities were compared by discrimination, calibration, and overall performance.
Based on 1,138 COVID-19 patients, the correlation between PSI-17 and PSI-20 was 0.95. Univariate logistic regression showed that PSI-17 had performance similar to PSI-20, based on AUC, ICI and Brier Score. After adjusting for confounding variables by multivariable logistic regression, PSI-17 and PSI-20 had AUCs (95% CI) of 0.85 (0.83-0.88) and 0.86 (0.84-0.89), respectively, indicating no significant difference in AUC at significance level of 0.05.
PSI-17 and PSI-20 are equally effective predictors of 30-day mortality in terms of several performance metrics. PSI-17 can be obtained without the manual chart review, which allows for automated risk calculations within an EMR. PSI-17 can be easily obtained and may be a comparable alternative to PSI-20.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
► New fatigue forged surface finish factor data to replace outdated historical data. ► Surface finish factor dependence on forging manufacturing parameters. ► Equation for surface finish factor as a ...function of hardness and fatigue life.
The overall objective of this study was to conduct a systematic and comprehensive experimental investigation to evaluate and quantify forged surface finish effect at several hardness levels (19 HRC, 25 HRC, 35 HRC, and 45 HRC) on fatigue behavior of a commonly used forged steel. Specimens were subjected to reversed cantilever bending and rotating bending fatigue. Two surface conditions were evaluated, a smooth-polished surface finish to be used as the reference surface, and a hot-forged surface finish. The heating methods used for forging were gas furnace heating as well as induction heating, to allow comparison of the two heating methods, as decarburization depth differs between the two methods. Since shot blasting is commonly used as a forged surface cleaning process with the additional benefit of inducing compressive residual stress, the hot-forged surface finish was evaluated with and without shot blasting. Limited amount of testing was also conducted to investigate the effect of the flash left by the forging process. Fatigue test results indicate that the historical data commonly used for the as-forged surface condition are overly conservative. New forged surface finish factors and curves as a function of hardness or tensile strength and fatigue life were developed based on experimental data.
Deletion of TRAF2 or TRAF3 in B cells prolongs their survival. However, it remains unknown whether deletion of such factors affects B cells' ability to tolerate DNA damage, which can be induced by ...chemotherapeutics and cause apoptosis. Genetic alterations of TRAF2 or TRAF3 are observed in subsets of human B-cell lymphomas and B cell-specific deletion of TRAF3 led to lymphoma development in aged mice. However, it remains unknown whether double deficiency of TRAF2 and TRAF3 accelerates B-cell lymphomagenesis. Here, we showed that B cell-specific TRAF2/3 double deficient (B-TRAF2/3-DKO) B cells were remarkably more resistant to DNA damage-induced apoptosis via upregulating cIAP2 and XIAP, which in turn attenuates caspase-3 activation. Mechanistically, resistance to DNA damage-induced apoptosis required NF-κB2, which effects by upregulating XIAP and cIAP2 transcription. B-TRAF2/3-DKO mice exhibited a shorter lifespan and succumbed to splenomegaly and lymphadenopathy. Unexpectedly, the incidence of B-cell lymphoma development in B-TRAF2/3-DKO mice was relatively rare (∼10%). Sequencing B cell receptor repertoire of diseased B cells revealed that TRAF2/3 deficiency caused abnormal oligoclonal or clonal expansion of B cells. While a fraction of mutant B cells (25-43%) from aged diseased mice harbored recurrent chromosomal translocations, primary B cells isolated from young B-TRAF2/3-DKO mice had no detectable chromosomal alterations, suggesting that TRAF2/3 deficiency per se does not cause evident genomic instability in B cells. Chemo-resistant TRAF3-deficient B-cell lymphomas were sensitized to chemotherapeutic drugs by blocking IAP activity using IAP antagonist. We conclude that double deficiency of TRAF2 and TRAF3 does not accelerate B-cell lymphomagenesis. Our studies provide insight into mechanisms regulating DNA damage-induced apoptosis and may help develop effective therapies targeting mutant B-cell lymphomas using IAP antagonist.
Thermal conductivity is one of the most crucial physical properties of matter when it comes to understanding heat transport, hydrodynamic evolution, and energy balance in systems ranging from ...astrophysical objects to fusion plasmas. In the warm dense matter regime, experimental data are very scarce so that many theoretical models remain untested. Here we present the first thermal conductivity measurements of aluminum at 0.5-2.7 g/cc and 2-10 eV, using a recently developed platform of differential heating. A temperature gradient is induced in a Au/Al dual-layer target by proton heating, and subsequent heat flow from the hotter Au to the Al rear surface is detected by two simultaneous time-resolved diagnostics. A systematic data set allows for constraining both thermal conductivity and equation-of-state models. Simulations using Purgatorio model or Sesame S27314 for Al thermal conductivity and LEOS for Au/Al release equation-of-state show good agreement with data after 15 ps. Discrepancy still exists at early time 0-15 ps, likely due to non-equilibrium conditions.
Allelic TERT promoter methylation and transcription scenarios in cancer:
1) biallelic wt; 2) monoallelic mutant; 3) monoallelic wt; 4) amplified mutant.
The transcriptional start site (angled arrow) ...and proximal (light blue) and distal (dark blue) TERT promoter regions with allele‐specific transcription levels are depicted. Unmethylated cytosine‐guanine dinucleotide (CpG) is green; methylated CpG is red.
C or T indicates a C‐>T TERT promoter mutation site.
Comment on: https://doi.org/10.1002/1878‐0261.12786
Telomerase regulation, including TERT promoter methylation, has been of long‐standing interest to cancer biologists. Rowland et al. have now vastly expanded their ongoing characterization of TERT promoter methylation in cancer cells, analyzing the methylation patterns of 833 cell lines from 23 human cancers. They document a highly conserved pattern of hypomethylation around the proximal promoter, as well as a more heterogeneous region of hypermethylation further upstream, both associated with active TERT expression in cancer cells. They further describe the interplay between activating TERT promoter mutations and allelic methylation and transcription patterns. This valuable dataset represents the most extensive characterization of TERT promoter methylation in cancer cells to date and will help guide the future study of transcriptional regulation of telomerase.
Comment on: https://doi.org/10.1002/1878‐0261.12786
A simple and effective means for obtaining hollow silica particles of controlled diameter from about 60 to 120 nm is presented. The synthesis utilizes equilibrium vesicles as templates for the ...directed growth of silica. Two different surfactant systems are used to form the vesicular templates: (a) mixtures of cetyltrimethylammonium bromide (CTAB) and sodium perfluorooctanoate (FC7) and (b) mixtures of cetyltrimethylammonium tosylate (CTAT) and sodium dodecylbenzenesulfonate (SDBS). These templates were chosen because these mixtures of surfactants in water form unilamellar vesicles spontaneously that appear stable in the chemical environment required for silica synthesis. Tetramethoxysilane (TMOS) is added to the vesicular templates as a precursor for silica formation via acid-catalyzed hydrolysis and polycondensation. The morphology of the silica products as observed with transmission electron microscopy (TEM), quasi-elastic light scattering (QLS), and small-angle neutron scattering (SANS) is consistent with silica deposition at the vesicle surface, creating hollow silica particles with a 1−2-nm-thick shell and with a core diameter identical to that of the template. TEM reveals under different conditions either discrete hollow particles or networks of linked or aggregated hollow silica shells.
The generation of low emittance electron beams from laser-driven wakefields is crucial for the development of compact x-ray sources. Here, we show new results for the injection and acceleration of ...quasimonoenergetic electron beams in low amplitude wakefields experimentally and using simulations. This is achieved by using two laser pulses decoupling the wakefield generation from the electron trapping via ionization injection. The injection duration, which affects the beam charge and energy spread, is found to be tunable by adjusting the relative pulse delay. By changing the polarization of the injector pulse, reducing the ionization volume, the electron spectra of the accelerated electron bunches are improved.
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