Phosphoinositide-3-kinase δ (PI3Kδ) is a critical regulator of cell growth and transformation and has been explored as a therapeutic target for a range of diseases. Through the exploration of the ...thienopyrimidine scaffold, we have identified a ligand-efficient methylation that leads to remarkable selectivity for PI3Kδ over the closely related isoforms. Interrogation through the Free–Wilson analysis highlights the innate selectivity the thienopyrimidine scaffold has for PI3Kδ and provides a predictive model for the activity against the PI3K isoforms.
Little is known about modifiable behaviours that may be associated with epithelial ovarian cancer (EOC) survival. We conducted a pooled analysis of 12 studies from the Ovarian Cancer Association ...Consortium to investigate the association between pre-diagnostic physical inactivity and mortality.
Participants included 6806 women with a primary diagnosis of invasive EOC. In accordance with the Physical Activity Guidelines for Americans, women reporting no regular, weekly recreational physical activity were classified as inactive. We utilised Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) representing the associations of inactivity with mortality censored at 5 years.
In multivariate analysis, inactive women had significantly higher mortality risks, with (HR=1.34, 95% CI: 1.18-1.52) and without (HR=1.22, 95% CI: 1.12-1.33) further adjustment for residual disease, respectively.
In this large pooled analysis, lack of recreational physical activity was associated with increased mortality among women with invasive EOC.
The synthesis, characterization, and oxidation reaction of a tropospherically relevant terpene bound to a glass surface are reported. Vibrational broadband sum frequency generation (SFG) is used to ...characterize the various terpene-modified glass surfaces and track their interaction with ozone. SFG spectra indicate that, although orientations of the surface-bound terpenes depend on the linker strategies employed, the CC double bond is accessible to gas-phase ozone regardless of the strategy applied. Exposure of the terpene-functionalized surface to ppm levels of ozone at 1 atm and 300 K yields an initial reaction probability of approximately 1 × 10-5 per surface collision, which is significantly higher than the corresponding gas-phase reaction involving 1-methyl-1-cyclohexene (5 × 10-7 from gas-phase collision theory). The interaction of ozone with a saturated octyl silane-functionalized glass surface leads to a slight molecular reorientation, or tilting, of the terminal CH3 groups on a much slower time scale. Our work demonstrates that SFG spectroscopy can be used to determine reaction probabilities of heterogeneous atmospheric reactions and bridges the gap between atmospheric chemistry and surface functionalization.
This final chapter of the Canadian Women’s Heart Health Alliance “ATLAS on the Epidemiology, Diagnosis, and Management of Cardiovascular Disease in Women” presents ATLAS highlights from the ...perspective of current status, challenges, and opportunities in cardiovascular care for women. We conclude with 12 specific recommendations for actionable next steps to further the existing progress that has been made in addressing these knowledge gaps by tackling the remaining outstanding disparities in women’s cardiovascular care, with the goal to improve outcomes for women in Canada.
Dans ce chapitre final de l’ATLAS sur l’épidémiologie, le diagnostic et la prise en charge de la maladie cardiovasculaire chez les femmes de l’Alliance canadienne de santé cardiaque pour les femmes, nous présentons les points saillants de l’ATLAS au sujet de l’état actuel des soins cardiovasculaires offerts aux femmes, ainsi que des défis et des occasions dans ce domaine. Nous concluons par 12 recommandations concrètes sur les prochaines étapes à entreprendre pour donner suite aux progrès déjà réalisés afin de combler les lacunes dans les connaissances, en s’attaquant aux disparités qui subsistent dans les soins cardiovasculaires prodigués aux femmes, dans le but d’améliorer les résultats de santé des femmes au Canada.
Early full-term pregnancy is one of the most effective natural protections against breast cancer. To investigate this effect, we have characterized the global gene expression and epigenetic profiles ...of multiple cell types from normal breast tissue of nulliparous and parous women and carriers of BRCA1 or BRCA2 mutations. We found significant differences in CD44+ progenitor cells, where the levels of many stem cell-related genes and pathways, including the cell-cycle regulator p27, are lower in parous women without BRCA1/BRCA2 mutations. We also noted a significant reduction in the frequency of CD44+p27+ cells in parous women and showed, using explant cultures, that parity-related signaling pathways play a role in regulating the number of p27+ cells and their proliferation. Our results suggest that pathways controlling p27+ mammary epithelial cells and the numbers of these cells relate to breast cancer risk and can be explored for cancer risk assessment and prevention.
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•Parity-related molecular alterations in control but not BRCA1/BRCA2 normal breast•Stem cell-related pathways are decreased in cells from parous women•Number of p27+ cells with progenitor features relates to breast cancer risk•p27 and TGF-β signaling are key regulators of mammary epithelial progenitors
Profiling of cell populations from the human mammary gland provides hints about differences in progenitors that may underlie the protective effect that early pregnancy has in reducing the risk for breast cancer.
Encourage or Discourage Listening Turon, Charles; Berenson, Gail; Dumlavwalla, Diana ...
The American music teacher,
02/2020, Letnik:
69, Številka:
4
Journal Article
Recenzirano
The familiarization with the piece needs to come from within, a kind of self-exploration, not influenced by others and devoid of informed decisions. ...I ask my students to follow 5 simple steps, ...after which they are encouraged to listen to several different recordings, discussing three elements they liked and disliked in them. 1. ...listening to good recordings is part of my curriculum and is critical at the beginning stages of learning new music. ...wonderful adults.
Thoracic x-ray computed tomography (CT) and hyperpolarized
He magnetic resonance imaging (MRI) provide quantitative measurements of airspace enlargement in patients with emphysema. For patients with ...panlobular emphysema due to alpha-1 antitrypsin deficiency (AATD), sensitive biomarkers of disease progression and response to therapy have been difficult to develop and exploit, especially those biomarkers that correlate with outcomes like quality of life. Here, our objective was to generate and compare CT and diffusion-weighted inhaled-gas MRI measurements of emphysema including apparent diffusion coefficient (ADC) and MRI-derived mean linear intercept (L
) in patients with AATD, chronic obstructive pulmonary disease (COPD) ex-smokers, and elderly never-smokers.
We enrolled patients with AATD (n = 8; 57 ± 7 years), ex-smokers with COPD (n = 8; 77 ± 6 years), and a control group of never-smokers (n = 5; 64 ± 2 years) who underwent thoracic CT, MRI, spirometry, plethysmography, the St. George's Respiratory Questionnaire, and the 6-minute walk test during a single 2-hour visit. MRI-derived ADC, L
, surface-to-volume ratio, and ventilation defect percent were generated for the apical, basal, and whole lung as was CT lung area ≤-950 Hounsfield units (RA
), low attenuating clusters, and airway count.
In patients with AATD, there was a significantly different MRI-derived ADC (P = .03), L
(P < .0001), and surface-to-volume ratio (P < .0001), but not diffusing capacity of carbon monoxide, residual volume or total lung capacity, or CT RA
(P > .05) compared to COPD ex-smokers with a significantly different St. George's Respiratory Questionnaire.
In this proof-of-concept demonstration, we evaluated CT and MRI lung emphysema measurements and observed significantly worse MRI biomarkers of emphysema in patients with AATD compared to patients with COPD, although CT RA
and diffusing capacity of carbon monoxide were not significantly different, underscoring the sensitivity of MRI measurements of AATD emphysema.
The complement system is a central component of host defense but can also contribute to the inflammation seen in pathological conditions. The C1s protease of the first complement component, the C1 ...complex, initiates the pathway. In this study we have elucidated the full specificity of the enzyme for the first time using a randomized phage display library. It was found that, aside from the crucial P1 position, the S3 and S2 subsites (in that order) played the greatest role in determining specificity. C1s prefers Leu or Val at P3 and Gly or Ala residues at P2. Apart from the S2′ position, which showed specificity for Leu, prime subsites did not greatly affect specificity. It was evident, however, that together they significantly contributed to the efficiency of cleavage of a peptide. A peptide substrate based on the top sequence obtained in the phage display validated these results and produced the best kinetics of any C1s substrate to date. The results allow an understanding of the active site specificity of the C1s protease for the first time and provide a basis for the development of specific inhibitors aimed at controlling inflammation associated with complement activation in adverse pathological situations.
Objective
The prevalence of MDR‐TB in Zambia was estimated to be 1.8% in 2001. A second drug resistance survey was conducted in 2008 to determine trends; the use of the Genotype MTBDRplus assay was ...applied to compare results to the gold standard.
Method
A two‐stage cluster sampling, with health facilities as primary sampling units. Processed sputum specimens were inoculated on solid media for culture; heat‐inactivated bacterial suspensions from sputum samples were tested on a commercial line probe assay for the identification of rifampicin and isoniazid resistance.
Results
A total of 917 patients with TB were enrolled and 883 (96.3%) analysed. A total of 574 (65%) had LJ results and 824 (93.3%) had results from MTBDRplus assay. The median age was 32, and 63.3% were males. MDR‐TB according to LJ‐based DST was 1.1% (CI 0.1–2.4) whereas according to MDTBDRplus assay was 1.6% (CI 0.6–2.6). Isoniazid monoresistance in new cases was 2.4% (CI 0.613–4.26) based on LJ results and 5.0% (CI 3.2–6.7) based on the MTBDRplus; in retreatment cases, it was 4.4% (CI 0.3–8.6) and 2.40% (CI <0.1–5.1) on LJ and MTBDRplus, respectively. Rifampicin monoresistance in new cases was 0.1% (CI <0.1–0.4) based on LJ and 0.6% (CI 0.01–1.1) based on the MTBDRplus; in retreatment cases, it was 0% (CI 0–3.8) and 1.8% (CI <0.1–4.0) on LJ and MTBDRplus, respectively. There were no XDR‐TB cases found and no association between MDR‐TB and HIV.
Conclusion
There was no increase in MDR‐TB prevalence in Zambia from 2001 to 2008; results from the two methods were similar. Molecular methods were quicker and simpler to use.
Objectif
La prévalence de la TB‐MDR en Zambie a été estimée à 1,8% en 2001. Une deuxième surveillance de la résistance aux médicaments a été menée en 2008 afin de déterminer les tendances; le test Genotype MTBDRplus a été utilisé pour comparer les résultats à ceux de la référence standard.
Méthode
Echantillonnage en grappes à deux étages, avec les établissements de santé comme unités primaires d’échantillonnage. Les échantillons d'expectoration traités ont été inoculés sur un milieu solide pour la culture, les suspensions bactériennes des échantillons de crachats inactivés par la chaleur ont été testées avec une sonde linéaire commerciale pour l'identification de la résistance à la rifampicine et à l'isoniazide.
Résultats
Un total de 917 patients TB ont été inscrits et 883 (96,3%) ont été analysés. 574 (65%) avaient des résultats par la culture sur LJ et 824 (93,3%) avaient des résultats avec le test MTBDRplus. L’âge médian était de 32 ans, 63,3% étaient des hommes. La TB‐MDR sur base des DST effectués sur LJ était de 1,1% (IC: 0,1 à 2,4) et de 1,6% (IC: 0,6 à 2,6) d'après le test MDTBDRplus). La mono‐résistance à l'isoniazide chez les nouveaux cas était de 2,4% (IC: 0,613 à 4,26) selon les résultats sur LJ et 5,0% (IC: 3,2 à 6,7) selon le test MTBDRplus; chez les cas de retraitement, elle était de 4,4% (IC: 0,3 à 8,6) et 2,40% (IC: <0,1 à 5,1) sur LJ et par MTBDRplus, respectivement. La mono‐résistance à la rifampicine chez les nouveaux cas était de 0,1% (IC: <0,1 à 0,4) selon les résultats sur LJ et 0,6% (IC: 0,01 à 1,1) selon le test MTBDRplus; chez les cas de retraitement, elle était de 0% (IC: 0 à 3,8) et 1,8% (IC: <0,1à 4,0) sur LJ et par MTBDRplus, respectivement. Aucun cas de TB‐UR et aucune association entre la TB‐MDR et le VIH n'on été trouvés.
Conclusion
Il n'y a pas eu d'augmentation de la prévalence de la TB‐MDR en Zambie entre 2001 et 2008; les résultats des deux méthodes étaient similaires. Les méthodes moléculaires étaient plus rapides et plus simples à utiliser.
Objetivo
Se calculó que la prevalencia de tuberculosis multirresistente (TB‐MR) en Zambia era 1.8% en el 2001. Se realizó un segundo estudio de resistencia a medicamentos en el 2008 para determinar tendencias; la prueba molecular Genotype MTBDRplus se utilizó para comparar los resultados con el patrón oro.
Método
Muestreo de conglomerados en dos etapas, con los centros sanitarios como unidades primarias de muestreo. Las muestras de esputo procesadas fueron inoculadas en medio de cultivo sólido: las suspensiones bacterianas inactivadas mediante calor, provenientes de las muestras de esputo, fueron analizadas utilizando pruebas comerciales estándar para determinar resistencias a rifampicina e isoniazida.
Resultado
De un total de 917 pacientes con TB en el estudio, 883 (96.3%) fueron analizados. 574 (65%) tenían resultados en Lowenstein‐Jensen (LJ) y 824 (93.3%) tenían resultados de la prueba MTBDRplus. La edad media era de 32 años, y un 63.3% eran hombres. La TB‐MR según la prueba LJ era del 1.1% (IC 0.1‐2.4) mientras que según el ensayo MDTBDRplus era del 1.6% (CI 0.6‐2.6). La mono‐resistencia a isoniazida entre nuevos casos era del 2.4% (IC 0.613‐4.26) basándose en los resultados de LJ y 5.0% (IC 3.2‐6.7) basándose en el MTBDRplus; en casos con retratamiento, era del 4.4% (IC 0.3‐8.6) y 2.4% (IC <0.1‐5.1) según LJ y MTBDRplus, respectivamente. La mono‐resistencia a rifampicina entre nuevos casos era del 0.1% (IC <0.1‐0.4) basándose en LJ y 0.6% (IC 0.01‐1.1) basándose en el MTBDRplus; en casos en retratamiento, era del 0% (IC 0‐3.8) y 1.8% (IC <0.1‐4.0) en LJ y MTBDRplus, respectivamente. No se encontraron casos de TB extremadamente resistente (TB‐XDR) y no existía asociación entre –TB‐MR y el VIH.
Conclusión
No había un aumento en la prevalencia de TB‐MR en Zambia entre 2001 y 2008; los resultados de los dos métodos eran similares. Los métodos moleculares eran más rápidos y más fáciles de utilizar.
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